Carboxylic acid derivatives that inhibit the binding of integrins to their receptors

ABSTRACT

A method for the inhibition of the binding of α 4 β 1  integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions comprising such compounds; and to the use of such compounds either a above, or in formulations for the control or prevention of diseases states in which α 4 β 1  is involved.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of U.S. patent application Ser. No.09/973,142 filed Oct. 9, 2001 now U.S. Pat. No. 6,972,296 which is acontinuation-in-part of U.S. patent application Ser. No. 09/707,068filed Nov. 6, 2000 now abandoned which is a continuation-in-part of U.S.application Ser. No. 09/565,920, filed May 5, 2000 now abandoned whichclaims the benefit of U.S. Provisional Patent Application Ser. No.60/132,971, filed May 7, 1999.

FIELD OF THE INVENTION

This invention is directed generally to the inhibition of the binding ofα₄β₁ integrin to its receptors, for example VCAM-1 (vascular celladhesion molecule-1) and fibronectin. The invention also relates tocompounds that inhibit this binding; to pharmaceutically activecompositions comprising such compounds; and to the use of such compoundseither as above, or in formulations for the control or prevention ofdisease states in which α₄β₁ is involved.

BACKGROUND OF THE INVENTION

When a tissue has been invaded by a microorganism or has been damaged,white blood cells, also called leukocytes, play a major role in theinflammatory response. One of the most important aspects of theinflammatory response involves the cell adhesion event. Generally, whiteblood cells are found circulating through the bloodstream. However, whena tissue is infected or becomes damaged, the white blood cells recognizethe invaded or damaged tissue, bind to the wall of the capillary andmigrate through the capillary into the affected tissue. These events aremediated by a family of proteins called cell adhesion molecules.

There are three main types of white blood cells: granulocytes, monocytesand lymphocytes. The integrin α₄β₁ (also called VLA-4 for very lateantigen-4) is a heterodimeric protein expressed on the surface ofmonocytes, lymphocytes and two subclasses of granulocytes: eosinophilsand basophils. This protein plays a key role in cell adhesion throughits ability to recognize and bind VCAM-1 and fibronectin, proteinsassociated with the endothelial cells that line the interior wall ofcapillaries.

Following infection or damage of tissue surrounding a capillary,endothelial cells express a series of adhesion molecules, includingVCAM-1, that are critical for binding the white blood cells that arenecessary for fighting infection. Prior to binding to VCAM-1 orfibronectin, the white blood cells initially bind to certain adhesionmolecules to slow their flow and allow the cells to “roll” along theactivated endothelium. Monocytes, lymphocytes, basophils and eosinophilsare then able to firmly bind to VCAM-1 or fibronectin on the bloodvessel wall via the α₄β₁ integrin. There is evidence that suchinteractions are also involved in transmigration of these white bloodcells into the damaged tissue as well as the initial rolling eventitself.

Although white blood cell migration to the site of injury helps fightinfection and destroy foreign material, in many instances this migrationcan become uncontrolled, with white blood cells flooding to the scene,causing widespread tissue damage. Compounds capable of blocking thisprocess, therefore, may be beneficial as therapeutic agents. Thus, itwould be useful to develop inhibitors that would prevent the binding ofwhite blood cells to VCAM-1 and fibronectin.

Some of the diseases that might be treated by the inhibition of α₄β₁binding include, but are not limited to, atherosclerosis, rheumatoidarthritis, asthma, allergy, multiple sclerosis, lupus, inflammatorybowel disease, graft rejection, contact hypersensitivity, and type Idiabetes. In addition to being found on some white blood cells, α₄β₁ isalso found on various cancer cells, including leukemia, melanoma,lymphoma and sarcoma cells. It has been suggested that cell adhesioninvolving α₄β₁ may be involved in the metastasis of certain cancers.Inhibitors of α₄β₁ binding may, therefore, also be useful in thetreatment of some forms of cancer.

The isolation and purification of a peptide which inhibits the bindingof α₄β₁ to a protein is disclosed in U.S. Pat. No. 5,510,332. Peptideswhich inhibit binding are disclosed in WO 95/15973, EP 0 341 915, EP 0422 938 A1, U.S. Pat. No. 5,192,746 and WO 96/06108. Novel compoundswhich are useful for inhibition and prevention of cell adhesion and celladhesion-mediated pathologies are disclosed in WO 96/22966, WO 98/04247and WO 98/04913.

It is therefore an object of the invention to provide novel compoundswhich are inhibitors of α₄β₁ binding, and pharmaceutical compositionsincluding such novel compounds.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula I

-   -   wherein Y, at each occurrence, is independently selected from        the group consisting of C(O), N, CR¹, C(R²)(R³), NR⁵, CH, O and        S;    -   q is an integer of from 3 to 10;    -   A is selected from the group consisting of O, S, C(R¹⁶)(R¹⁷) and        NR⁶;    -   E is selected from the group consisting of CH₂, O, S, and NR⁷;    -   J is selected from the group consisting of O, S and NR⁸;    -   T is selected from the group consisting of C(O) and (CH₂)_(b)        wherein b is an integer of from 0 to 3;    -   M is selected from the group consisting of C(R⁹)(R¹⁰) and        (CH₂)_(u), wherein u is an integer of from 0 to 3;    -   L is selected from the group consisting of O, NR¹¹, S, and        (CH₂)_(n) wherein n is an integer of 0 or 1;    -   X is selected from the group consisting of CO₂B, PO₃H₂, SO₃H,        SO₂NH₂, SO₂NHCOR¹², OPO₃H₂, C(O)NHC(O)R¹³, C(O)NHSO₂R¹⁴,        hydroxyl, tetrazolyl and hydrogen;    -   W is selected from the group consisting of C, CR¹⁵ and N; and    -   B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴,        R¹⁵, R¹⁶ and R¹⁷ at each occurrence are independently selected        from the group consisting of hydrogen, halogen, alkyl, alkenyl,        alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl,        aliphatic acyl, —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂, —OH,        alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃-alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)—NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;        -   wherein B, R¹, R², R³, R⁴, R⁵, R⁶, R₇, R⁸, R⁹, R¹⁰, R¹¹,            R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are unsubstituted or            substituted with at least one electron donating or electron            withdrawing group;        -   wherein when L is NR¹¹, R⁴ and R¹¹ taken together may form a            ring;        -   and wherein when M is C(R₉)(R¹⁰), R₉ and R¹⁰ taken together            may form a ring;        -   and wherein when A is NR and at least one Y is CR¹, R¹ and            R⁶ taken together may form a ring;    -   or a pharmaceutically acceptable salt thereof;    -   with the proviso that when A is C(R¹⁶)(R¹⁷), E is not NR⁷.

For Formula I, presently preferred compounds may have A as NR⁶; E asNR⁷; J as O; M as C(R⁹)(R¹⁰); q as 4 or 5; T as (CH₂)_(b) wherein b is0; L as (CH₂)_(n) wherein n is 0; X as CO₂B; W as C or CR¹⁵; R⁴ as aryl,alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl orheterocyclylalkyl; and R₆, R₇, R₉, R¹⁰ and R¹⁵ independently as hydrogenor lower alkyl.

More specifically, the compounds of this invention may be described byFormula II

-   -   wherein Y, at each occurrence, is independently selected from        the group consisting of C(O), N, CR¹, C(R²)(R³), NR₅, CH, O and        S;    -   q is an integer of from 3 to 7;    -   T is selected from the group consisting of C(O) and (CH₂)_(b)        wherein b is an integer of 0 to 3;    -   L is selected from the group consisting of O, NR¹¹, S, and        (CH₂)_(n) wherein n is an integer of 0 or 1;    -   W is selected from the group consisting of C, CR¹⁵ and N; and    -   B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹ and R¹⁵ are        independently selected from the group consisting of hydrogen,        halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,        thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF₃, —CO₂H, —SH, —CN,        —NO₂, —NH₂, —OH, alkynylamino, alkoxycarbonyl, heterocycloyl,        carboxy, —N(C₁-C₃ alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃        alkyl)C(O)NH(C₁-C₃ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃        alkyl), —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;        -   wherein B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹ and R¹⁵            are unsubstituted or substituted with at least one electron            donating or electron withdrawing group;        -   wherein when L is NR¹¹, R⁴ and R¹¹ taken together may form a            ring;            -   and wherein R⁹ and R¹⁰ taken together may form a ring;            -   and wherein when at least one Y is CR¹, R¹ and R⁶ taken                together may form a ring;    -   or a pharmaceutically acceptable salt thereof.

For Formula II, presently preferred compounds may have q as 4 or 5; W asC or CR¹⁵; T as (CH₂)_(b) wherein b is 0; L as (CH₂)_(n) wherein n is 0;R⁴ as aryl, alkylaryl, aralkyl, heterocyclyl, alkylheterocyclyl orheterocyclylalkyl; and R⁶, R⁷, R⁹, R¹⁰ and R¹⁵ as independently hydrogenor lower alkyl.

More specifically, the compounds of this invention may be described byFormula III

-   -   wherein Y, at each occurrence, is independently selected from        the group consisting of C(O), N, CR¹, C(R²)(R³), NR⁵, CH, O and        S;    -   q is an integer of from 2 to 5;    -   T is selected from the group consisting of C(O) and (CH₂)_(b)        wherein b is an integer of 0 to 3;    -   L is selected from the group consisting of O, NR¹¹, S, and        (CH₂)_(n) wherein n is an integer of 0 or 1;    -   R⁵, R⁶, R⁷, R¹¹ and R¹⁸ are each independently selected from the        group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl,        aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl,        —CH═NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,        cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,        aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,        heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and        —C(O)NH(benzyl) groups; and    -   B, R¹, R², R³, R⁴, R⁹ and R¹⁰ are independently selected from        the group consisting of hydrogen, halogen, alkyl, alkenyl,        alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl,        aliphatic acyl, —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂, —OH,        alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;        -   wherein B, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹ and R¹⁸            are unsubstituted or substituted with at least one electron            donating or electron withdrawing group;        -   wherein when L is NR¹¹, R⁴ and R¹¹ taken together may form a            ring;        -   and wherein R⁹ and R¹⁰ taken together may form a ring;        -   and wherein when at least one Y is CR¹, R¹ and R⁶ taken            together may form a ring;    -   or a pharmaceutically acceptable salt thereof.

For Formula III, presently preferred compounds may have R¹⁸ as hydrogen,alkyl, aryl, aralkyl, cycloalkyl, alkylheterocyclyl, heterocyclylalkylor heterocyclyl; T as (CH₂)_(b) wherein b is 0; L as (CH₂)_(n) wherein nis 0; Y as CR¹ and C(R²)(R³) and q as 2 or 3.

In Formula III, the portion of the molecule

and pharmaceutical acceptable salts thereof and pharmaceuticalacceptable salts thereof

-   -   wherein R₁₉, R₂₀, R²¹ and R₂₈ at each occurrence are        independently selected from the group consisting of halogen,        alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy,        hydroxyalkyl, aliphatic acyl, —CF₃, —OH, —CO₂H, —SH, —CN, —NO₂,        —NH₂, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy,        —N(C₁-C₃ alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃        alkyl)C(O)NH(C₁-C₃ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃        alkyl), —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;    -   R¹⁸ is selected from the group consisting of alkyl, alkenyl,        alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino,        alkoxycarbonyl, heterocycloyl, —CH═NOH, haloalkyl, alkoxyalkoxy,        carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl,        cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,        biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,        aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,        carbamate, aryloxyalkyl, hydrogen and —C(O)NH(benzyl) groups;    -   R²² is selected from the group consisting of hydrogen, halogen,        alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy,        hydroxyalkyl, aliphatic acyl, —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂,        —OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy,        —N(C₁-C₃ alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃        alkyl)C(O)NH(C₁-C₃ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃        alkyl), —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;    -   c is an integer of zero to two;    -   d is an integer of zero to three;    -   e is an integer of zero to four; and    -   i is an integer of zero to two.        In one embodiment, R¹⁸ is aralkyl; R⁴ is aryl; T is (CH₂)_(b)        where b is zero; L is (CH₂)_(n) where n is zero; and, B, R⁶, R⁷,        R⁹ and R¹⁰ are each independently hydrogen.

More specifically, the compounds of this invention may be described byFormula IV

-   -   wherein T is selected from the group consisting of C(O) and        (CH₂)_(b) wherein b is an integer of from 0 to 3;    -   L is selected from the group consisting of O, NR¹¹, S, and        (CH₂)_(n) wherein n is an integer of 0 or 1;    -   g is an integer of from 0 to 7;    -   B, R⁴, R⁹, R¹⁰ and R²³ at each occurrence are independently        selected from the group consisting of hydrogen, halogen, alkyl,        alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy,        hydroxyalkyl, aliphatic acyl, —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂,        —OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy,        —N(C₁-C₃ alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃        alkyl)C(O)NH(C₁-C₃ alkyl)-NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃        alkyl), —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups; and    -   R⁶, R⁷, R¹¹ and R¹⁸ are each independently selected from the        group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl,        aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl,        —CH═NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,        cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,        aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,        heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and        —C(O)NH(benzyl) groups;    -   wherein B, R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹⁸ and R²³ are        unsubstituted or substituted with at least one electron donating        or electron withdrawing group;        -   wherein when L is NR¹¹, R⁴ and R¹¹ taken together may form a            ring;        -   and wherein R⁹ and R¹⁰ taken together may form a ring;            or a pharmaceutically acceptable salt thereof.

Presently preferred compounds of the present invention may also bedescribed by Formula V.

-   -   wherein h is an integer of zero to five;    -   B, R⁹, R¹⁰, R²⁴, and R²⁵ are each independently selected from        the group consisting of hydrogen, halogen, alkyl, alkenyl,        alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl,        aliphatic acyl, —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂, —OH,        alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;    -   R²⁷, at each occurrence, is independently selected from the        group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy,        alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,        —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂, —OH, alkynylamino,        alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), —N(C₁-C₃ alkyl)SO₂(C₁-C₃ alkyl), —N(C₁-C₃        alkyl)SO₂(aryl), —C alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;    -   R⁶, R⁷ and R¹⁸ are each independently selected from the group        consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic        acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, —CH═NOH,        haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,        cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,        aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,        heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and        —C(O)NH(benzyl) groups; and,    -   R²⁶ is selected from the group consisting of hydrogen, alkyl,        alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, —CF₃,        alkoxycarbonyl, heterocycloyl, carboxy, —C(O)O—(C₁-C₃)alkyl,        —C(O)NH—(C₁-C₃)alkyl, —C(O)N(C₁-C₃ alkyl)₂, —PO₃H₂, haloalkyl,        carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl,        cycloalkylalkyl, aryl, aroyl, biaryl, heterocyclyl, alkylaryl,        aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,        sulfonyl, —SO₂—(C₁-C₃ alkyl), sulfonamido, aryloxyalkyl and        —C(O)NH(benzyl) groups;    -   wherein B, R⁶, R⁷, R⁹, R¹⁰, R¹⁸, R²⁴, R²⁵, R²⁶ and R²⁷ are        unsubstituted or substituted with at least one electron donating        or electron withdrawing group;        -   wherein R¹⁸ and R²⁴ taken together may form a ring;        -   R²⁴ and R²⁵ taken together may form a ring;        -   R²⁵ and R²⁶ taken together may form a ring;        -   and wherein R⁹ and R¹⁰ taken together may form a ring;            or a pharmaceutically acceptable salt thereof.            Presently preferred compounds of Formula V have B, R⁶, R⁷,            R⁹, R¹⁰, R²⁴, R²⁵ and R²⁶ each independently hydrogen and            R¹⁸ as substituted or unsubstituted aralkyl.

Other presently preferred compounds of the present invention may bedescribed by Formula VI.

-   -   wherein Z, at each occurrence, is independently selected from        the group consisting of C(O), N, CR³⁰, C(R³¹)(R³²), NR³³, CH, O        and S;    -   z is an integer of from 3 to 6;    -   k is an integer of from 0 to 5;    -   T is selected from the group consisting of C(O) and (CH₂)_(b)        wherein b is an integer of from 0 to 3;    -   L is selected from the group consisting of O, NR¹¹, S, and        (CH₂)_(n) wherein n is an integer of 0 or 1;    -   R⁶, R⁷, R¹¹, R¹⁸ and R³³ are each independently selected from        the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl,        aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl,        —CH═NOH, haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,        cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,        aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,        heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and        —C(O)NH(benzyl) groups;    -   B, R⁴, R⁹, R¹⁰, R³⁰, R³¹ and R³² at each occurrence are        independently selected from the group consisting of hydrogen,        halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy,        thioalkoxy, hydroxyalkyl, aliphatic acyl, —CF₃, —CO₂H, —SH, —CN,        —NO₂, —NH₂, —OH, alkynylamino, alkoxycarbonyl, heterocycloyl,        carboxy, —N(C₁-C₃ alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃        alkyl)C(O)NH(C₁-C₃ alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃        alkyl), —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups; and,    -   R²⁹, at each occurrence, is independently selected from the        group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy,        alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,        —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂, —OH, alkynylamino,        alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;    -   wherein B, R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹⁸, R²⁹, R³⁰, R³¹, R³² and        R³³ are        -   unsubstituted or substituted with at least one electron            donating or electron withdrawing group;        -   wherein when L is NR¹¹, R⁴ and R¹¹ taken together may form a            ring;        -   and wherein R⁹ and R¹⁰ taken together may form a ring;            or a pharmaceutically acceptable salt thereof.

Some compounds of Formulae I-VI can be prepared from novel intermediatesof Formula VII and Formula VIII.

-   -   wherein R²⁴ and R²⁵ are each independently selected from the        group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,        alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic        acyl, —CF₃, —SH, —OH, —CO₂H, —CN, —NO₂, —NH₂, alkynylamino,        alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), alkylamino, —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), alkoxyalkyl, alkenylamino, di(C₁-C₃)amino,        —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl, —C(O)N(C₁-C₃ alkyl)₂,        —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl, alkoxyalkoxy,        carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl,        cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,        biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,        aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,        sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃ alkyl), sulfonamido,        carbamate, aryloxyalkyl and —C(O)NH(benzyl) groups; and    -   R¹⁸ and R³⁴ are each independently selected from the group        consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic        acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, —CH═NOH,        haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide,        cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl,        aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino,        heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, carbamate, aryloxyalkyl, hydrogen and        —C(O)NH(benzyl) groups;        -   wherein R¹⁸, R²⁴, R²⁵ and R³⁴ are unsubstituted or            substituted with at least one electron donating or electron            withdrawing group;        -   and wherein R²⁴ and R²⁵ taken together may form a ring; with            the proviso that when R²⁴ and R²⁵ taken together form a            ring, the ring formed is not benzene. Presently preferred            compounds of Formula VII have R³⁴ as hydrogen; R¹⁸ as            aralkyl; and R²⁴ and R²⁵ each independently as hydrogen,            lower alkyl or lower alkyl wherein R²⁴ and R²⁵ are taken            together to form a ring.

Formula VIII shows presently preferred novel intermediates.

-   -   wherein R²⁴ and R²⁵ are each independently selected from the        group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl,        alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic        acyl, —CF₃, —SH, —OH, —CO₂H, —CN, —NO₂, —NH₂, alkynylamino,        alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;    -   R³⁴ is selected from the group consisting of alkyl, alkenyl,        alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino,        alkoxycarbonyl, heterocycloyl, —CH═NOH, haloalkyl, alkoxyalkoxy,        carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl,        cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino,        biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl,        aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl,        carbamate, aryloxyalkyl, hydrogen and —C(O)NH(benzyl) groups;        and,    -   R³⁵, at each occurrence, is independently selected from the        group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy,        alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,        —CF₃, —CO₂H, —SH, —CN, —NO₂, —NH₂, —OH, alkynylamino,        alkoxycarbonyl, heterocycloyl, carboxy, —N(C₁-C₃        alkyl)-C(O)(C₁-C₃ alkyl), —NHC(O)N(C₁-C₃ alkyl)C(O)NH(C₁-C₃        alkyl), —NHC(O)NH(C₁-C₆ alkyl), —NHSO₂(C₁-C₃ alkyl),        —NHSO₂(aryl), alkoxyalkyl, alkylamino, alkenylamino,        di(C₁-C₃)amino, —C(O)O—(C₁-C₃)alkyl, —C(O)NH—(C₁-C₃)alkyl,        —C(O)N(C₁-C₃ alkyl)₂, —CH═NOH, —PO₃H₂, —OPO₃H₂, haloalkyl,        alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl,        cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl,        aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl,        alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl,        heterocyclylalkyl, sulfonyl, —SO₂—(C₁-C₃ alkyl), —SO₃—(C₁-C₃        alkyl), sulfonamido, carbamate, aryloxyalkyl and —C(O)NH(benzyl)        groups;        -   wherein R²⁴, R²⁵, R³⁴ and R³⁵ are unsubstituted or            substituted with at least one electron donating or electron            withdrawing group; and,    -   m is an integer of from 0 to 5. Presently preferred compounds of        Formula VIII have R³⁴ as hydrogen; m as an integer of one to        three and R³⁵ at each occurrence as alkyl, halogen, alkoxy,        haloalkyl, sulfonyl, —OH or —CN.

Presently preferred compounds of Formula I include:(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(phenylmethyl)-4-propyl-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[4-(methyloxy)phenyl]propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3,4-dimethylphenyl)propanoicacid,(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(1,4-oxazinan-4-yl)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4-(propylamino)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-bromophenyl)methyl]-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(methyloxy)phenyl]propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(2-{[2-(methyloxy)ethyl]oxy}ethyl)oxy]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-yridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(1,1-dimethylethyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-phenylpropanoicacid, (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[4-methyltetrahydro-1(2H)-pyrazinyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[4-(methyloxy)phenyl]propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3,5-dimethylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(3-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(methyloxy)phenyl]propanoicacid,(3S)-3-[3,5-bis(methyloxy)phenyl]-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(trifluoromethyl)phenyl]propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({4-(1-azetanyl)-1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-yridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-({2-[(2-{[2-(methyloxy)ethyl]oxy}ethyl)oxy]ethyl}oxy)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chloro-6-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-(1,3-benzodioxol-5-yl)-3-((((2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)-1,2dihydro-3-pyridinyl)amino)carbonyl)amino)propanoic acid,(3S)-3-((((1-((2-chlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoicacid,(3S)-3-((((1-((2-fluorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoicacid,(3S)-3-((((1-((2-bromophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoicacid,(3S)-3-((((1-((2,4-dichlorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoicacid,(3S)-3-((((1-((2-chloro-6-fluorophenyl)methyl)-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-methylphenyl)propanoicacid,(3S)-3-((((1-((2-chlorophenyl)methyl)-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl)amino)carbonyl)amino)-3-(4-trifluoromethyl)oxy)phenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,4-{[3-[({[(1S)-2-carboxy-1-(4-methylphenyl)ethyl]amino}carbonyl)amino]-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl]amino}benzoicacid,(3S)-3-{[({1-(2-chlorobenzyl)-4-[(2,2-dimethylpropanoyl)amino]-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(7-methoxy-1,3-benzodioxol-5-yl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxy-4-methoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-dimethoxyphenyl)propanoicacid,(3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2,6-difluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethoxy-4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-dimethylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-[({([1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2,6-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoicacid,(3S)-3-(3-butoxyphenyl)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]propanoicacid,(3S)-3-{[({1-[2-chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(2-methoxyethoxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-dipropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(difluoromethoxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-cyanobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2-naphthyl)propanoicacid and(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-diethoxyphenyl)propanoicacid,(3S)-3-[({[5-chloro-1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-phenylpropanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(trifluoromethoxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-5-methoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-6-yl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropyloxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(difluoromethyl)oxy]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(1,1,2,2-tetrafluoroethyl)oxy]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1-ethyl-1H-indol-5-yl)propanoicacid and(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3-(diethylamino)phenyl]propanoicacid, and(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1H-indol-5-yl)propanoicacid and pharmaceutically acceptable salts thereof of the abovecompounds.

Presently preferred compounds of Formula VII include:5-(2-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-fluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-fluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-benzyl-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-benzyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,5-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,4-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,5-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-chloro-5-(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-fluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-5-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[3,5-bis(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-tert-butylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(3-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[3-(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-bromobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(3,4-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[4-(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(3-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(pyridin-2-ylmethyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-methyl-3,5-dihydro-[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,4-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,6-difluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[3-(trifluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[4-(trifluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(3-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,3-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(3,5-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-pentyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,4-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,7-butyl-5-(2-chlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-chloro-5-(trifluoromethyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,6-dichlorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-5-fluorobenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione,7-methyl-5-[4-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,4-[(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide,5-(mesitylmethyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-3,5,6,7,8,9-hexahydro[1,3]oxazolo[4,5-c]quinoline-2,4-dione,5-(2-chlorobenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,2-[(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]-N,N-dimethylbenzenesulfonamide,5-(2,6-dimethoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-(trifluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-chloro-5-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-chloro-2-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-5,6,7,8,9,10-hexahydro-2H-cyclohepta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione,5-[2-(difluoromethoxy)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,7-methyl-5-[(1R)-1-phenylethyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(4-chlorobenzyl)-7-propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,6-dimethylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,3-chloro-2-[(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile,5-(2-chloro-6-methylbenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,2-[(2,4-dioxo-2,3-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl)methyl]benzonitrile,5-(2-chloro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[3-(methylthio)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-cyclopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(3-chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,6-dichlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,7-methyl-5-(4-methylbenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(3,5-dimethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,6-difluorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[3-(methylsulfonyl)benzyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-fluoro-6-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-methoxybenzyl)-7-propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(5-chloro-2-fluorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-isopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(5-fluoro-2-methylbenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,7-methyl-5-[(1S)-1-phenylethyl]-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-5-isopropoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(5-acetyl-2-methoxybenzyl)-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione,5-[2-fluoro-6-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-methylbenzyl)-5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione,5-(2-chloro-6-ethoxybenzyl)-7-ethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-propoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-isobutoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione,5-(2-chloro-6-isopropoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-chloro-6-(2,2,2-trifluoroethoxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione,5-[2-chloro-6-(2-methoxyethoxy)benzyl]-5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione,5-(2-chloro-6-ethoxybenzyl)-6,7-dimethyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-7-ethyl-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chlorobenzyl)-7-ethyl-3,5-dihydro[1,3]oxazolo[4,5-d]pyridazine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-7-propyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-7-cyclopropyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-5-propoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-5-methoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-6-ethoxybenzyl)-6-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2-chloro-5-ethoxybenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-chloro-5-(piperidin-1-ylsulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-chloro-5-(pyrrolidin-1-ylsulfonyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-chloro-6-(cyclopentylmethoxy)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-[2-(benzyloxy)-6-chlorobenzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione,5-(2,3-dichloro-6-ethoxybenzyl)-5,6,7,8-tetrahydro-2H-cyclopenta[b][1,3]oxazolo[5,4-d]pyridine-2,4(3H)-dione,5-[2-chloro-5-(trifluoromethyl)benzyl]-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dioneand5-(2-chloro-5-fluorobenzyl)-7-methyl-3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione.

Derivatives such as esters, carbamates, aminals, amides, optical isomersand pro-drugs are also contemplated.

The present invention also relates to pharmaceutical compositionscomprising a physiologically acceptable diluent and at least onecompound of the present invention.

The present invention further relates to a process of inhibiting thebinding of α₄β₁ integrin to VCAM-1 comprising exposure of a cellexpressing α₄β₁ integrin to a cell expressing VCAM-1 in the presence ofan effective inhibiting amount of a compound of the present invention.The VCAM-1 may be on the surface of a vascular endothelial cell, anantigen presenting cell, or other cell type. The α₄β₁ may be on a whiteblood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; orany other cell that naturally expresses α₄β₁.

The invention also provides a method for treating disease statesmediated by α₄β₁ binding which comprises administration of an effectiveamount of a compound of the present invention, either alone or informulation, to an afflicted patient.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms

The term “alkyl” as used herein, alone or in combination, refers toC₁-C₁₂ straight or branched, substituted or unsubstituted saturatedchain radicals derived from saturated hydrocarbons by the removal of onehydrogen atom, unless the term alkyl is preceded by a C_(x)-C_(y)designation. Representative examples of alkyl groups include methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, andtert-butyl among others.

The term “alkenyl” as used herein, alone or in combination, refers to asubstituted or unsubstituted straight-chain or substituted orunsubstituted branched-chain alkenyl radical containing from 2 to 10carbon atoms. Examples of such radicals include, but are not limited to,ethenyl, E- and Z-pentenyl, decenyl and the like.

The term “alkynyl” as used herein, alone or in combination, refers to asubstituted or unsubstituted straight or substituted or unsubstitutedbranched chain alkynyl radical containing from 2 to 10 carbon atoms.Examples of such radicals include, but are not limited to ethynyl,propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

The term “lower” modifying “alkyl”, “alkenyl”, “alkynyl” or “alkoxy”refers to a C₁-C₆ unit for a particular functionality. For example loweralkyl means C₁-C₆ alkyl.

The term “aliphatic acyl” as used herein, alone or in combination,refers to radicals of formula alkyl-C(O)—, alkenyl-C(O)— andalkynyl-C(O)— derived from an alkane-, alkene- or alkyncarboxylic acid,wherein the terms “alkyl”, “alkenyl” and “alkynyl” are as defined above.Examples of such aliphatic acyl radicals include, but are not limitedto, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl,crotyl, propiolyl and methylpropiolyl, among others.

The term “cycloalkyl” as used herein refers to an aliphatic ring systemhaving 3 to 10 carbon atoms and 1 to 3 rings, including, but not limitedto cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl amongothers. Cycloalkyl groups can be unsubstituted or substituted with one,two or three substituents independently selected from lower alkyl,haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy,halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl andcarboxamide.

“Cycloalkyl” includes cis or trans forms. Furthermore, the substituentsmay either be in endo or exo positions in the bridged bicyclic systems.

The term “cycloalkenyl” as used herein alone or in combination refers toa cyclic carbocycle containing from 4 to 8 carbon atoms and one or moredouble bonds. Examples of such cycloalkenyl radicals include, but arenot limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl and thelike.

The term “cycloalkylalkyl” as used herein refers to a cycloalkyl groupappended to a lower alkyl radical, including, but not limited tocyclohexylmethyl.

The term “halo” or “halogen” as used herein refers to I, Br, Cl or F.

The term “haloalkyl” as used herein refers to a lower alkyl radical, towhich is appended at least one halogen substituent, for examplechloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl amongothers.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term “alkyl” is as defined above.Examples of suitable alkyl ether radicals include, but are not limitedto, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like.

The term “alkoxyalkyl” as used herein, refers to R_(y)—O—R_(z), whereinR_(y) is lower alkyl as defined above, and R_(z) is alkylene(—(CH₂)_(w)—) wherein w is an integer of from one to six. Representativeexamples include methoxymethyl, methoxyethyl, and ethoxyethyl amongothers.

The term “alkenoxy” as used herein, alone or in combination, refers to aradical of formula alkenyl-O, provided that the radical is not an enolether, wherein the term “alkenyl” is as defined above. Examples ofsuitable alkenoxy radicals include, but are not limited to, allyloxy, E-and Z-3-methyl-2-propenoxy and the like.

The term “alkynoxy” as used herein, alone or in combination, refers to aradical of formula alkynyl-O, provided that the radical is not an -ynolether. Examples of suitable alkynoxy radicals include, but are notlimited to, propargyloxy, 2-butynyloxy and the like.

The term “carboxy” as used herein refers to —C(O)O—.

The term “thioalkoxy” refers to a thioether radical of formula alkyl-S—,wherein “alkyl” is as defined above.

The term “sulfonamido” as used herein refers to —SO₂NH₂.

The term “carboxaldehyde” as used herein refers to —C(O)R wherein R ishydrogen.

The terms “carboxamide” or “amide” as used herein refer to—C(O)NR_(a)R_(b) wherein R_(a) and R_(b) are each independentlyhydrogen, alkyl or any other suitable substituent.

The term “alkoxyalkoxy” as used herein refers to R_(c)O—R_(d)O— whereinR_(c) is lower alkyl as defined above and R_(d) is alkylene whereinalkylene is —(CH₂)_(n′)— wherein n′ is an integer from 1 to 6.Representative examples of alkoxyalkoxy groups include methoxymethoxy,ethoxymethoxy, t-butoxymethoxy among others.

The term “alkylamino” as used herein refers to R_(e)NH— wherein R_(e) isa lower alkyl group, for example, ethylamino, butylamino, among others.

The term “alkenylamino” as used herein, alone or in combination, refersto a radical of formula alkenyl-NH— or (alkenyl)₂N—, wherein the term“alkenyl” is as defined above, provided that the radical is not anenamine. An example of such alkenylamino radical is the allylaminoradical.

The term “alkynylamino” as used herein, alone or in combination, refersto a radical of formula alkynyl-NH— or (alkynyl)₂N— wherein the term“alkynyl” is as defined above, provided that the radical is not anamine. An example of such alkynylamino radicals is the propargyl aminoradical.

The term “dialkylamino” as used herein refers to R_(f)R_(g)N— whereinR_(f) and R_(g) are independently selected from lower alkyl, for examplediethylamino, and methyl propylamino, among others.

The term “alkoxycarbonyl” as used herein refers to an alkoxyl group aspreviously defined appended to the parent molecular moiety through acarbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl,ethoxycarbonyl, and isopropoxycarbonyl among others.

The term “aryl” or “aromatic” as used herein alone or in combinationrefers to a substituted or unsubstituted carbocyclic aromatic grouphaving about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl,indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromaticgroup containing at least one endocyclic N, O or S atom such as furyl,thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl,benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxyazinyl, pyrazolo[1,5-c]triazinyl and the like. “Aralkyl” and“alkylaryl” employ the term “alkyl” as defined above. Rings may bemultiply substituted.

The term “aralkyl” as used herein, alone or in combination, refers to anaryl substituted alkyl radical, wherein the terms “alkyl” and “aryl” areas defined above. Examples of suitable aralkyl radicals include, but arenot limited to phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl,pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl,indolylmethyl, thienylpropyl and the like.

The term “aralkenyl” as used herein, alone or in combination, refers toan aryl substituted alkenyl radical, wherein the terms “aryl” and“alkenyl” are as defined above.

The term “arylamino” as used herein, alone or in combination, refers toa radical of formula aryl-NH—, wherein “aryl” is as defined above.Examples of arylamino radicals include, but are not limited to,phenylamino(anilido), naphthlamino, 2-, 3-, and 4-pyridylamino and thelike.

The term “benzyl” as used herein refers to C₆H₅—CH₂—.

The term “biaryl” as used herein, alone or in combination, refers to aradical of formula aryl-aryl, wherein the term “aryl” is as definedabove.

The term “thioaryl” as used herein, alone or in combination, refers to aradical of formula aryl-S—, wherein the term “aryl” is as defined above.An example of a thioaryl radical is the thiophenyl radical.

The term “aroyl” as used herein, alone or in combination, refers to aradical of formula aryl-CO—, wherein the term “aryl” is as definedabove. Examples of suitable aromatic acyl radicals include, but are notlimited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl,pyridylcarbonyl and the like.

The term “heterocyclyl” as used herein, alone or in combination, refersto a non-aromatic 3- to 10-membered ring containing at least oneendocyclic N, O, or S atom. The heterocycle may be optionallyaryl-fused. The heterocycle may also optionally be substituted with atleast one substituent which is independently selected from the groupconsisting of hydrogen, halogen, hydroxyl, amino, nitro,trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl,aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl andaralkylaminocarbonyl among others.

The term “alkylheterocyclyl” as used herein refers to an alkyl group aspreviously defined appended to the parent molecular moiety through aheterocyclyl group, including but not limited to 2-methyl-5-thiazolyl,2-methyl-1-pyrrolyl and 5-ethyl-2-thienyl.

The term “heterocyclylalkyl” as used herein refers to a heterocyclylgroup as previously defined appended to the parent molecular moietythrough an alkyl group, including but not limited to 2-thienylmethyl,2-pyridinylmethyl and 2-(1-piperidinyl)ethyl.

The term “heterocycloyl” as used herein refers to radicals of theformula heterocyclyl-C(O)—, wherein the term “heterocyclyl” is asdefined above.

The term “aminal” as used herein refers to a hemi-acetal of thestructure R_(h)C(NR_(i)R_(j))(NR_(k)R_(l))— wherein R_(h), R_(i), R_(j),R_(k) and R_(l) are each independently hydrogen, alkyl or any othersuitable substituent.

The term “ester” as used herein refers to —C(O)R_(m), wherein R_(m) ishydrogen, alkyl or any other suitable substituent.

The term “carbamate” as used herein refers to compounds based oncarbamic acid NH₂C(O)OH.

The term “optical isomers” as used herein refers to compounds whichdiffer only in the stereochemistry of at least one atom, includingenantiomers, diastereomers and racemates.

Use of the above terms is meant to encompass substituted andunsubstituted moieties. Substitution may be by one or more groups suchas alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl,nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy,lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy,trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy,carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl andaralkylaminocarbonyl or any of the substituents of the precedingparagraphs or any of those substituents either attached directly or bysuitable linkers. The linkers are typically short chains of 1-3 atomscontaining any combination of —C—, —C(O)—, —NH—, —S—, —S(O)—, —O—,—C(O)O— or —S(O)O—. Rings may be substituted multiple times.

The terms “electron-withdrawing” or “electron-donating” refer to theability of a substituent to withdraw or donate electrons relative tothat of hydrogen if hydrogen occupied the same position in the molecule.These terms are well-understood by one skilled in the art and arediscussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18,incorporated herein by reference. Electron withdrawing groups includehalo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde,carboxyamido, aryl, quaternary ammonium, trifluoromethyl, sulfonyl andaryl lower alkanoyl among others. Electron donating groups include suchgroups as hydroxy, lower alkyl, amino, lower alkylamino, di(loweralkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto,and disulfide among others. One skilled in the art will appreciate thatthe aforesaid substituents may have electron donating or electronwithdrawing properties under different chemical conditions. Moreover,the present invention contemplates any combination of substituentsselected from the above-identified groups.

The most preferred electron donating or electron withdrawingsubstituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl,aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide,heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, loweralkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino,lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto,mercaptoalkyl, alkylthio, carboxy lower alkyl, arylalkoxy,alkanoylamino, alkanoyl(lower alkyl)amino, lower alkylsufonylamino,arylsulfonylamino, alkylsulfonyl(lower alkyl)amino, arylsulfonyl(loweralkyl)amino, lower alkylcarboxamide, di(lower alkyl)carboxamide,sulfonamide, lower alkylsulfonamide, di(lower alkyl)sulfonamide, loweralkylsulfonyl, arylsulfonyl and alkyldithio.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

As used herein, the term “mammals” includes humans and other animals.The ring defined by Y in Formulae I, II and III can be a mono-cyclicheterocycle or aromatic ring, or can be a bicyclic ring.

The dotted lines used in Formulae I, II, III, IV and VI indicate thatthe bond at that location can be either single or double. The bondbetween the atoms Y and W for example can be a single or double bond ifY and/or W is a substitutent such as N, C or CH. Therefore, the ringdefined by Y in the Formulae can be either saturated or unsaturated,depending upon which W and/or Y is selected. In Formulae IV and VI, thedotted line indicates that the nitrogen-containing ring optionallycontains double bonds at the indicated locations.

In the Formulae, certain R groups potentially substitute theirassociated rings a number of times. R¹⁹, R²⁰, R²¹, R²³, R²⁷, R²⁸, R²⁹and R²⁵ may each substitute their associated rings more than once. Forexample for R¹⁹, when c is zero, the associated ring is unsubstituted,having hydrogens at the C-2 and C-4 positions; and for R²³, when g iszero, hydrogens are at the C-2-C-5 positions.

Suitable substituents for the aryl, alkyl, cycloalkyl, heterocyclylgroups or the ring defined by Y and W in the formulae described above,when present, include alcohols, amines, heteroatoms, or any combinationof aryl, alkoxy, alkoxyalkoxy, alkyl, cycloalkyl or heterocyclyl groupseither attached directly, or via suitable linkers. The linkers aretypically short chains of 1-3 atoms containing any combination of C,C═O, CO₂, O, N, S, S═O, SO₂, as for example ethers, amides, amines,ureas, sulfamides, sulfonamides, among others.

For example, R¹, R², R³, R⁵, R⁶, R⁷ and R⁸ in the above formulae mayindependently be, but are not limited to: hydrogen, alkyl, phenyl,thienylmethyl, isobutyl, n-butyl, 2-thienylmethyl,1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl,3-methyl-1-benzothiophen-2-yl, allyl, 3-methoxybenzyl, propyl,2-ethoxyethyl, cyclopropylmethyl, benzylsulfanylmethyl,benzylsulfonylmethyl, phenylsulfanylmethyl, phenethylsulfanylmethyl,3-phenylpropylsulfanylmethyl, 4-((2-toluidinocarbonyl)amino)benzyl,2-pyridinylethyl, 2-(1H-indol-3-yl)ethyl, 1H-benzimidazol-2-yl,4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-hydroxyphenethyl,4-aminobenzyl, phenylsulfonylmethyl, 4-(acetylamino)phenyl,4-methoxyphenyl, 4-aminophenyl, 4-chlorophenyl,(4-(benzylsulfonyl)amino)phenyl, (4-(methylsulfonyl)amino)phenyl,2-aminophenyl, 2-methylphenyl, isopropyl, 2-oxo-1-pyrrolidinyl,3-(methylsulfanyl)propyl, (propylsulfanyl)methyl, octylsulfanylmethyl,3-aminophenyl, 4-((2-toluidinocarbonyl)amino)phenyl,2-((methylbenzyl)amino)benzyl, methylsulfanylethyl, hydroxy, chloro,fluoro, bromo, ureido, amino, methanesulfonylamino, acetylamino,ethylsulfanylmethyl, 2-chlorobenzyl, 2-bromobenzyl, 2-fluorobenzyl,2-chloro-6-fluorobenzyl, 2-chloro-4-fluorobenzyl, 2,4-dichlorobenzyl,2-chloro-6-methoxybenzyl, 2-cyanobenzyl, 2,6-difluorobenzyl,2-chloro-5-(trifluoromethyl)benzyl, 2-chloro-6-methylbenzyl,2,6-dimethoxybenzyl, 2-chloro-5-(methylsulfonyl)benzyl,2-chloro-6-cyanobenzyl, 2-chloro-6-ethoxybenzyl,2-chloro-5-methoxybenzyl, 2-chloro-5-fluorobenzyl,5-chloro-2-fluorobenzyl, ethyl, propyl, butyl, pentyl, cyclopropyl,tert-butylamino, propylamino, 4-methyl-1-piperazinyl, 1-azetidinyl,4-morpholino, (4-carboxyphenyl)amino, pivaloylamino,((tert-butylamino)carbonyl)amino, trifluoromethyl, benzyloxy,2-(2-methoxyethoxy)ethoxy, 2-(2-(2-methoxyethoxy)ethoxy)ethoxy and2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy.

The R⁴ substituent for the formulae above may be, but is not limited to1,3-benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl,2,6-dimethylphenyl, allyloxyphenyl, 3-bromo-4-methoxyphenyl,4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl,methylsulfanyl, phenylsulfanyl, phenethylsulfanyl, 4-bromo-2-thienyl,3-methyl-2-thienyl, 4-methylphenyl, 3,5-bis(methyloxy)phenyl,4-(methyloxy)phenyl, 4-fluorophenyl, 3-(methyloxy)phenyl,3,4,5-tris(methyloxy)phenyl, 2,3-dihydro-1-benzofuran-5-yl,3-fluorophenyl, 4-(trifluoromethyl)phenyl,4-fluoro-3-(trifluoromethyl)phenyl, 4-(1,1,1-dimethylethyl)phenyl,3,5-dimethylphenyl, 4-hydroxyphenyl, 3,4-dimethylphenyl,3-methyl-4-(methyloxy)phenyl, 4-hydroxy-3-methylphenyl, 3-methylphenyl,2,3-dihydro-inden-5-yl, 2-methylphenyl, 2,6-bis(methyloxy)phenyl,2,6-dihydroxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl,4-((trifluoromethyl)oxy)phenyl, 4-ethylphenyl, 4-(ethyloxy)phenyl,methyl, 2-propyl, 4,5-dihydro-1,3-oxazol-2-yl,3-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,2,3-dihydro-1,4-benzodioxin-6-yl, 7-methoxy-1,3-benzodioxol-5-yl,3-ethoxy-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl,3-ethoxyphenyl, 3-methoxy-4-methylphenyl, 3,5-dimethoxy-4-methylphenyl,3-propoxyphenyl, 3-butoxyphenyl, 3-(2-methoxyethoxy)phenyl,3,4-dipropoxyphenyl, 3-(difluoromethoxy)phenyl, 2-naphthyl,3-isopropoxyphenyl, 1-methyl-1H-indol-5-yl,2,3-dihydro-1-benzofuran-5-yl,1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl,3-(trifluoromethoxy)phenyl, 1-methyl-1H-indol-6-yl,3-(cyclopropoxy)phenyl, 3-(cyclopropylmethoxy)phenyl,3-(difluoromethoxy)phenyl, 3-(1,1,2,2-tetrafluoroethoxy)phenyl,1-ethyl-1H-indol-5-yl, 3-(diethylamino)phenyl, 6-methoxy-2-naphthyl,3-[(methylsulfonyl)amino]phenyl, 3-[methyl(methylsulfonyl)amino]phenyl,3-[ethyl(methylsulfonyl)amino]phenyl, 1H-indol-5-yl,3-fluoro-4-methoxyphenyl and 3-(difluoromethyl)phenyl.

Two independent R¹, R², R³ or R⁵ groups taken together may be linked toform a ring.

R⁴ and R¹¹ may be linked to form a ring such as 1-pyrrolidino,1-piperidino, 4-methyl-1-piperazino, 4-acetyl-1-piperazino and4-morpholino among others.

R⁹ and R¹⁰ may be linked to form a ring such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl among others.

Abbreviations

Abbreviations which have been used in the schemes and the examples whichfollow are: BOC for t-butyloxycarbonyl; DMF for dimethylformamide; THFfor tetrahydrofuran; DME for dimethoxyethane; DMSO fordimethylsulfoxide; NMM for N-methyl morpholine; DIPEA fordiisopropylethylamine; CDI for 1,1′-carbonyldiimidazole; TBS forTRIS-buffered saline; Ms for methanesulfonyl, TMEDA forN,N,N′,N′-tetramethylethylenediamine, DCE for 1,2-dichloroethane, NCSfor N-chlorosuccinimide, NBS for N-bromosuccinimide, DPPA fordiphenylphosphorylazide, DEAD for diethyl azodicarboxylate, m-CPBA for3-chloroperoxybenzoic acid, TFAA for trifluoroacetic anhydride, DCM fordichloromethane, LHMDS for lithium bis(trimethylsilyl)amide and Cbz forbenzyloxycarbonyl. Amino acids are abbreviated as follows: C forL-cysteine; D for L-aspartic acid; E for L-glutamic acid; G for glycine;H for L-histidine; I for L-isoleucine; L for L-leucine; N forL-asparagine; P for L-proline; Q for L-glutamine; S for L-serine; T forL-threonine; V for L-valine and W for L-tryptophan.

Examples of the procedures that may be used to synthesize compounds ofthe Formulae described above are shown in the Schemes which follow. Adetailed description of the representative compounds of the presentinvention is set forth in the Examples below.

Scheme 1 below illustrates the procedure described in Example 1.

Scheme 2, illustrating the procedure of Example 2, is shown below.

Scheme 3, illustrating the procedure of Example 3, is shown below.

Scheme 4, illustrating the procedure of Example 4, is shown below.

Scheme 5, illustrating the procedure of Example 5, is shown below.

Scheme 6, illustrating the procedure of Example 6, is shown below.

Scheme 7, illustrating the procedure of Example 7, is shown below.

Scheme 8, illustrating the procedure of Example 8, is shown below.

Scheme 9, illustrating the procedure of Example 9, is shown below.

Scheme 10, illustrating the procedure of Example 10, is shown below.

Scheme 11, illustrating the procedure of Example 11, is shown below.

Scheme 12, illustrating the procedure of Example 12, is shown below.

Scheme 13, illustrating the procedure of Example 13, is shown below.

Scheme 14, illustrating the procedure of Example 14, is shown below.

Scheme 15, illustrating the procedure of Example 15, is shown below.

Scheme 16, illustrating the procedure of Example 16, is shown below.

Scheme 17, illustrating the procedure of Example 17, is shown below

Scheme 18, illustrating the procedure of Example 18, is shown below.

Scheme 19, illustrating the procedure of Example 19, is shown below.

Scheme 20, illustrating the procedure of Example 20, is shown below.

Scheme 21, illustrating the procedure of Example 21, is shown below.

Scheme 22, illustrating the procedure of Example 22, is shown below.

Scheme 23, illustrating the procedure of Example 23, is shown below.

Scheme 24, illustrating the procedure of Example 24, is shown below.

Scheme 25, illustrating the procedure of Example 25, is shown below.

Scheme 26, illustrating Example 26 is shown below.

Scheme 27, illustrating Example 27, is shown below.

Scheme 28, illustrating Example 28, is shown below.

Scheme 29, illustrating Example 29, is shown below.

Scheme 30, illustrating Example 30, is shown below.

Scheme 31, illustrating Example 31, is shown below.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be preparedin situ during the final isolation and purification of the compounds ofthe invention or separately by reacting a free base function with asuitable organic acid. Representative acid addition salts include, butare not limited to acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which canbe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. Alternatively, the compound can beadministered as a pharmaceutical composition containing the compound ofinterest in combination with one or more pharmaceutically acceptableexcipients. The phrase “therapeutically effective amount” of thecompound of the invention means a sufficient amount of the compound totreat disorders, at a reasonable benefit/risk ratio applicable to anymedical treatment. It will be understood, however, that the total dailyusage of the compounds and compositions of the present invention will bedecided by the attending physician within the scope of sound medicaljudgement. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.0001 to about 1000mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.001 to about 5 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions can be specially formulated for oraladministration in solid or liquid form, for parenteral injection or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a component of the present invention and aphysiologically tolerable diluent. The present invention includes one ormore compounds as described above formulated into compositions togetherwith one or more non-toxic physiologically tolerable or acceptablediluents, carriers, adjuvants or vehicles that are collectively referredto herein as diluents, for parenteral injection, for intranasaldelivery, for oral administration in solid or liquid form, for rectal ortopical administration, among others.

The compositions can also be delivered through a catheter for localdelivery at a target site, via an intracoronary stent (a tubular devicecomposed of a fine wire mesh), or via a biodegradable polymer. Thecompounds may also be complexed to ligands, such as antibodies, fortargeted delivery.

Compositions suitable for parenteral injection may comprisephysiologically acceptable, sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), vegetable oils (such asolive oil), injectable organic esters such as ethyl oleate, and suitablemixtures thereof.

These compositions can also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present inventionwhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. Prodrugs of the present invention may be rapidlytransformed in vivo to the parent compound of the above formula, forexample, by hydrolysis in blood. A thorough discussion is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of theA.C.S. Symposium Series, and in Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press (1987), hereby incorporated by reference.

Compounds of the present invention that are formed by in vivo conversionof a different compound that was administered to a mammal are intendedto be included within the scope of the present invention.

Compounds of the present invention may exist as stereoisomers whereinasymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The present invention contemplates various stereoisomersand mixtures thereof. Stereoisomers include enantiomers anddiastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of the present invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

In another aspect, the present invention contemplates a process ofinhibiting the binding of α₄β₁ integrin to VCAM-1. A process of thepresent invention can be used either in vitro or in vivo. In accordancewith a process of the present invention, a cell expressing α₄β₁ integrinis exposed to a cell expressing VCAM-1 in the presence of an effectiveinhibiting amount of a compound of the present invention.

A cell expressing α₄β₁ integrin can be a naturally occurring white bloodcell, mast cell or other cell type that naturally expresses α₄β₁ on thecell surface, or a cell transfected with an expression vector thatcontains a poly-nucleotide (e.g., genomic DNA or cDNA) that encodes α₄β₁integrin. In an especially preferred embodiment, α₄β₁ integrin ispresent on the surface of a white blood cell such as a monocyte, alymphocyte or a granulocyte (e.g., an eosinophil or a basophil).

A cell that expresses VCAM-1 can be a naturally occurring cell (e.g. anendothelial cell) or a cell transfected with an expression vectorcontaining a polynucleotide that encodes VCAM-1. Methods for producingtransfected cells that express VCAM-1 are well known in the art.

Where VCAM-1 exists on the surface of cell, the expression of thatVCAM-1 is preferably induced by inflammatory cytokines such as tumornecrosis factor-α interleukin-4 and interleukin-1β.

Where the cells expressing α₄β₁ integrin and VCAM-1 are in a livingorganism, a compound of the present invention is administered in aneffective amount to the living organism. Preferably, the compound is ina pharmaceutical composition of this invention.

A process of the present invention is especially useful in treatingdiseases associated with uncontrolled migration of white blood cells todamaged tissue. Such diseases include, but are not limited to, asthma,atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis,lupus, inflammatory bowel disease, graft rejection, contacthypersensitivity, type I diabetes, leukemia, and brain cancer.Administration is preferably accomplished via intravascular,subcutaneous, intranasal, transdermal or oral delivery.

The present invention also provides a process of selectively inhibitingthe binding of α₄β₁ integrin to a protein comprising exposing theintegrin to the protein in the presence of an effective inhibitingamount of a compound of the present invention. In a preferredembodiment, the α₄β₁ integrin is expressed on the surface of a cell,either naturally occurring or a cell transformed to express α₄β₁integrin.

The protein to which the α₄β₁ integrin binds can be expressed either ona cell surface or be part of the extracellular matrix. Especiallypreferred proteins are fibronectin or invasin.

The ability of compounds of the present invention to inhibit binding isdescribed in detail hereinafter in the Examples. These Examples arepresented to describe preferred embodiments and utilities of theinvention and are not meant to limit the invention unless otherwisestated in the claims appended hereto.

The ability of compounds of the present invention to inhibit binding isdescribed in detail hereinafter in the Examples. These Examples arepresented to describe preferred embodiments and utilities of theinvention and are not meant to limit the invention unless otherwisestated in the claims appended hereto.

EXAMPLE 1 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (10)

Step One: Compound 1 (20.8 g, 135 mmol) was dissolved in methanol (270mL) and palladium on carbon (10% Pd dry weight basis, Degussa type E101NE/W, ˜50% water content, 5.75 g, 2.7 mmol Pd) was added. The atmospherewas replaced with hydrogen (toggle between vacuum and hydrogen from aballoon five times), the mixture was stirred overnight, then filtered.The filtrate was concentrated under vacuum and the residue was taken upin a 1:1 hexanes:ethyl acetate mixture and washed with a 4:1 mixture ofwater and saturated NaHCO₃, saturated NaHCO₃ and brine. The organiclayer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give compound 2 (12.43 g, 74%) asa white solid. This material was used without purification.

Step Two: Compound 2 (2.64 g, 21.3 mmol) was dissolved indichloromethane (50 mL) and chilled to 0° C. The cold solution wastreated sequentially with triethylamine (3.6 mL, 25.6 mmol) andtrimethylacetyl chloride (2.90 mL, 23.4 mmol). The solution was stirredat room temperature for 6 hours, then refluxed overnight. The mixturewas partitioned between dichloromethane and aqueous NaOH (2N). Theorganic layer was washed with brine, dried over MgSO₄ and filtered andthe filtrate was concentrated to give compound 3 (3.33 g, 75%).

Step Three: Compound 3 (0.50 g, 2.4 mmol) was dissolved in dry THF, (9.6mL) and TMEDA (1.1 mL, 7.2 mmol) under a dry nitrogen atmosphere. Theresulting solution was chilled to between −20 and −10° C. and treatedsequentially with n-butyllithium (1.6 M in hexanes 2.25 mL) andt-butyllithium (1.7 M in pentane, 2.1 mL) dropwise via syringe. After 30minutes the bath temperature was allowed to come to −5 to 0° C. andtreated with ethyl iodide via a syringe (0.77 mL, 9.6 mmol). Thesolution was stirred at 0° C. for 2 hours, then room temperatureovernight. The mixture was quenched with methanol and concentrated todryness. The residue was purified by filtering through silica gel,eluting with 3:1 hexanes:ethyl acetate and then recrystallizing fromhexanes to yield compound 4 (0.32 g, 56%).

Step Four: Compound 4 (0.32 g, 1.3 mmol) was dissolved in glacial aceticacid (4.5 mL) and treated with potassium iodide (0.65 g, 3.9 mmol). Theresulting mixture was heated in an oil bath regulated at 115° C. for 1.0hour. The mixture was cooled, diluted with water and adjusted to pH 6using 2N NaOH and 2N HCl. The mixture was extracted with chloroform (4times). The combined extracts were washed with aqueous sodiumthiosulfate, dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure to give compound 5 (0.25 g, 86%) asa white solid. This material was used without further purification.

Step Five: Compound 5 (0.25 g, 1.1 mmol) was dissolved in THF (45 mL)and treated dropwise with a solution of potassiumbis(trimethylsilyl)amide (0.5 M in toluene, 2.7 mL) at 0° C. Theresulting solution was treated with 2-chlorobenzylbromide (0.16 mL, 1.2mmol) and the solution was allowed to warm to room temperatureovernight. The mixture was partitioned between 2N HCl and ethyl acetate.The organic layer was washed with brine, dried over MgSO₄ and filtered.The filtrate was concentrated under reduced pressure and the residue waspurified by chromatography (SiO₂, gradient elution 4:1 switching to 2:1hexanes:ethyl acetate) to give compound 6 (0.16 g, 41%).

Step Six: Compound 6 (0.16 g, 0.46 mmol) was suspended in 1:1water:concentrated HCl (4.6 mL). The suspension was brought to refluxfor 4 hours, during which time the compound dissolved. The mixture wascooled, diluted with water and extracted with diethyl ether. The aqueouslayer adjusted basic with excess saturated sodium bicarbonate solution,and the mixture was extracted with ethyl acetate. The extracts werecombined, washed with brine, dried over MgSO₄ and filtered. The filtratewas concentrated under reduced pressure to give compound 7 (0.081 g,67%).

Step Seven: Compound 7 (0.080 g, 0.30 mmol) was dissolved in1,2-dichloroethane (1.2 mL) and DIPEA (0.115 mL, 0.66 mmol) and chilledto 0° C. The cold solution was treated rapidly with a solution ofphosgene (1.93 M in toluene, 0.170 mL, 0.33 mmol). After 30 minutes asolution of compound 8 (0.068 g, 0.33 mmol) in 1,2-dichloroethane (0.5mL) was added rapidly via syringe. The resulting mixture was heated to55° C. for 1 hour. The mixture was partitioned between dichloromethaneand 2N HCl. The organic layer was washed with saturated aqueous NaHCO₃and brine, dried over MgSO₄ and filtered. The filtrate was concentratedto give compound 9 (0.110 g, 74%).

Step Eight: Compound 9 (0.11 g, 0.22 mmol) was dissolved in 2:1 THF:H₂O(0.88 mL) and treated with a solution of 2N NaOH (0.33 mL). Methanol wasadded dropwise until a homogeneous solution was obtained. The mixturewas stirred for 20 minutes, diluted with water and washed with ethylether. The aqueous layer was acidified with 2N HCl and extracted withethyl acetate. The ethyl acetate layer was washed with brine, dried overMgSO₄ and filtered. The filtrate was concentrated to give(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (10, 0.095 g, 92%).

EXAMPLE 2 Synthesis of(3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (15)

Step One: To a suspension of compound 11 (1.0 g, 5.9 mmol) and K₂CO₃(2.40 g 17.6 mmol) in acetone (50 mL) was added benzylbromide (2.31 g,13.5 mmol). After refluxing overnight, the reaction was cooled and themixture was partitioned between ethyl acetate and saturated NaHCO₃. Theorganic layer was washed with dilute HCl and brine, dried over MgSO₄ andfiltered and the filtrate was concentrated to give compound 12 (1.60 g,80%).

Step Two: Compound 12 (0.30 g, 0.86 mmol), zinc powder (0.30 g, 4.6mmol) and saturated aqueous NH₄Cl (0.30 mL) were mixed in MeOH (18 mL).This mixture was allowed to stir at room temperature for 1 hour beforeadditional zinc (0.30 g, 4.6 mmol) was added. The resultingheterogeneous mixture was refluxed overnight. After filtration of thehot mixture and concentration of the filtrate under reduced pressure,the residue was dissolved in ethyl acetate and washed with saturatedaqueous NaHCO₃ and brine. The organic layer was dried over MgSO₄ andfiltered and the filtrate was concentrated under reduced pressure togive compound 13 (0.18 g, 66%).

Step Three: Compound 13 (0.30 g, 0.94 mmol.) and DIPEA (0.40 mL, 2.3mmol.) were dissolved in CH₂Cl₂ and the mixture was cooled to 0° C.Phosgene (1.9 M in toluene, 0.55 mL, 1.0 mmol) was added to the solutiondropwise. The reaction mixture was stirred at 0° C. for 15 minutesbefore compound 8 (0.19 g, 0.94 mmol) in CH₂Cl₂ (2 mL) was added. Theresulting solution was stirred at room temperature overnight then pouredinto ethyl acetate and washed with saturated aqueous NaHCO₃, 1 N HCl andbrine. The organic layer was dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel, eluting with 1:1increasing to 1:2 hexanes:ethyl acetate to give compound 14 (0.33 g,64%).

Step Four: A solution of compound 14 (0.33 g, 0.6 mmol) in THF (6 mL)was treated with 2N NaOH (2 mL). MeOH was added until homogeneoussolution was achieved. The reaction mixture was stirred at roomtemperature for 30 minutes and poured into H₂O (50 mL). The aqueouslayer was washed with diethyl ether (twice), and then acidified with 1NHCl. The aqueous layer was extracted with ethyl acetate (twice). Thecombined ethyl acetate extracts were washed with brine (twice), driedover MgSO₄ and filtered. The filtrate was concentrated under reducedpressure to give(3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4-[(phenylmethyl)oxy]-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (15, 0.26 g, 90%) as an off-white solid. Melting point: 124-126° C.

EXAMPLE 3 Synthesis of(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (22)

Step One: To a solution of compound 11 (10.00 g, 58.8 mmol) in anhydrousDMF (120 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 5.40g, 135 mmol). The mixture was stirred at 0° C. for 15 minutes before theaddition of 2-chlorobenzylchloride (12.3 g, 76.4 mmol). After stirringat 55° C. overnight, the mixture was poured into ice-water and washedwith Et₂O twice. The aqueous layer was acidified and filtration of theresulting precipitate gave compound 16 (14.7 g, 85%).

Step Two: To a flask containing compound 16 (8.00 g, 28.6 mmol) sealedwith a rubber septum and balloon at room temperature under dry nitrogenatmosphere, POCl₃ (30.0 ml, 322 mmol) was added via syringe. Thenitrogen line was removed and the reaction mixture was stirred overnightat 70° C., then poured over ice (300 ml) and stirred for 30 minutes. Theresulting mixture was extracted with dichloromethane (300 ml) and theorganic phase was dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure to give compound 17 (7.3 g, 86%) asa dark brown solid.

Step Three: To a 250 ml flask equipped with condenser and rubber septumfitted with a balloon, a solution of compound 17 (2.1 g, 7.05 mmol),methanol (55 ml) and aqueous ammonium hydroxide (28-30%, 70.0 ml, 1.14mol) were added at room temperature. The reaction mixture was heated to65° C. for 60 hours open only to the balloon. The mixture was filteredand the filtrate was concentrated under reduced pressure to yieldcompound 18 (1.5 g, 76%) as a brown solid.

Step Four: To a solution of compound 18 (0.3 g, 1.02 mmol) in methanol(50 ml) at room temperature, saturated aqueous ammonium chloride (2 ml)and zinc dust (0.30 g, 4.6 mmol) were added sequentially. After stirring30 minutes at room temperature, additional zinc was added (0.30 g, 4.6mmol) and the reaction mixture was refluxed overnight. The reactionmixture was filtered hot and the filtrate was concentrated under reducedpressure. The residue was partitioned between ethyl acetate and 1N NaOH.The solution was filtered and the aqueous phase extracted with ethylacetate. The combined organic phases were dried over MgSO₄ and filtered.The filtrate was concentrated under reduced pressure to yield compound19 (0.21 g, 78%) as a brown solid.

Step Five: A solution of compound 19 (0.10 g, 0.38 mmol), NMM (0.040 mL,0.38 mmol) and compound 20 (0.14 g, 0.38 mmol) in anhydrous DMF (5 mL)was heated to 50° C. overnight. The mixture was cooled and diluted withethyl acetate (60 mL). The organic layer was washed with 0.5N NaOH (3×30mL) and brine, dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified byflash chromatography on silica gel, eluting with 9:1 increasing to 17:3CHCl₃:MeOH to give compound 21 (0.120 g, 65%) as a yellow foam.

Step Six: A solution of compound 21 (0.120 g, 0.25 mmol) in THF (6 mL)was treated with 2N NaOH (2 mL). Methanol was added until a homogeneoussolution was achieved. The reaction mixture was stirred at roomtemperature for 30 minutes and poured into H₂O (50 mL). The aqueouslayer was washed with diethyl ether (twice), and then acidified with 1NHCl. The aqueous layer was extracted with ethyl acetate (twice). Thecombined ethyl acetate extracts were washed with brine (twice), driedover MgSO₄ and filtered. The filtrate was concentrated under reducedpressure to give(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)-carbonyl]amino}-3-(4-methylphenyl)propanoicacid (22, 0.100 g, 89%) as an off-white solid. Melting point: 145-147°C.

EXAMPLE 4 Synthesis of(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(methyloxy)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: To a solution of compound 23 (10.00 g, 64.0 mmol) in anhydrousDMF (130 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 5.90g, 147 mmol). The mixture was stirred at 0° C. for 15 minutes before theaddition of 2-chlorobenzylchloride (13.4 g, 83.3 mmol). After stirringat 55° C. overnight, the mixture was poured into ice water and washedwith Et₂O (twice). The aqueous layer was acidified and filtration of theresulting precipitate gave compound 24 (13.5 g, 75%).

Step Two: A suspension of compound 24 (1.0 g, 3.6 mmol), K₂CO₃ (0.85 g,6.2 mmol) and MeI (1.18 g, 8.3 mmol) in acetone (20 mL) was refluxedovernight. The reaction mixture was diluted with ethyl acetate andwashed with saturated aqueous NaHCO₃, 1N HCl and brine. The organiclayer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give Compound 25 (0.74 g, 70%).

(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(methyloxy)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was prepared from compound 25 according to procedures described inExample 3. MS: Calculated: (M+H)⁺=469.93; Found: (M+H)⁺=470.01.

EXAMPLE 5 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid

Step One: Compound 3 (0.65 g, 3.1 mmol) was dissolved in dry THF (12.4mL) and TMEDA (0.90 mL, 6 mmol) under a dry nitrogen atmosphere. Theresulting solution was chilled to between −15 and −10° C. andn-butyllithium (1.6 M in hexanes, 7.75 mL, 12.4 mmol) was added dropwisevia syringe. After 1.5 hours, a solution of N-fluorobenzenesulfonimide(1.07 g, 3.4 mmol) in THF (5 mL) was added to the cold solution rapidlyvia syringe. The solution was stirred at 0° C. for 1 hour, then roomtemperature for 3 hours. The mixture was quenched with water andextracted with chloroform (4 times). The combined organic extracts werewashed with brine, dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography, (SiO₂, plug gel, using 4:1 switching to 3:1hexanes:ethyl acetate) to yield compound 26 (0.177 g, 25%).

(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-fluoro-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid was prepared from Compound 26 according to procedures described inExample 1. MS: Calculated: (M+H)⁺=458.12; Found: (M+H)⁺=458.01.

EXAMPLE 6 Synthesis of(3S)-4-chloro-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid

Step One: Compound 3 (0.65 g, 3.1 mmol) was dissolved in THF (21 mL) andTMEDA (1.20 mL, 7.75 mmol) and chilled to −15° C. The solution wastreated with n-butyllithium (1.6 M in hexanes, 4.8 mL, 7.8 mmol). Themixture was maintained between −20 and −10° C. for 1 hour, then cooledto −78° C. Solid N-chlorosuccinimide (0.45 g, 3.4 mmol) was added whilethe apparatus was under a positive flow of nitrogen. The reaction wasallowed to gradually warm to room temperature then stirred overnight.The mixture was quenched with water and extracted with chloroform (4times). The organic layers were combined, dried over MgSO₄ and filtered.The filtrate was concentrated under reduced pressure and the residue wasrecrystallized from hexanes to give compound 27 (0.25 g, 33%).

(3S)-4-Chloro-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid was prepared from compound 27 according to procedures described inExample 1.

EXAMPLE 7 Synthesis of(3S)-4-bromo-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid

Step One: Compound 3 (2.00 g, 9.6 mmol) was dissolved in dry THF (32 mL)and TMEDA (2.20 mL, 14.4 mmol) under a dry nitrogen atmosphere. Theresulting solution was chilled to between −20 and −10° C. and n-butyllithium (1.60 M in hexanes, 18.0 mL, 28.8 mmol) was added dropwise viasyringe. Upon completion of the addition, the solution was chilled to−78° C. and bromine (0.49 mL, 10.5 mmol) was added dropwise via syringe.The solution was allowed to warm slowly to room temperature overnight,then was quenched with water and extracted with chloroform. The organiclayer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure. The residue was recrystallized fromhexanes to give compound 28 (1.32 g, 48%) as a tannish white solid.

(3S)-4-Bromo-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid was prepared from compound 28 according to procedures described inExample 1.

EXAMPLE 8 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (32)

Step One: To a solution of compound 24 (1.5 g, 5.3 mmol) in methanol (50ml) at room temperature, saturated ammonium chloride (1.5 mL) and zincdust (1.5 g, 23 mmol) were added sequentially. After stirring 30 minutesat room temperature, additional zinc dust (1.5 g, 23 mmol) was added andthe reaction mixture was refluxed overnight. The reaction mixture wasfiltered while hot and the filtrate was concentrated under reducedpressure. HCl (1 N) was added to the resulting residue until the pH wasapproximately 4 and the resulting precipitate was collected byfiltration to give compound 29 (0.80 g, 57%) as a brown solid.

Step Two: A solution of compound 29 (0.26 g, 1.0 mmol) and CDI (0.25 g,1.6 mmol) in DMF (10 mL) was heated to 70° C. overnight. After coolingto room temperature, the mixture was diluted with ethyl acetate andwashed with 1N HCl (3 times) and brine. The organic layer was dried overMgSO₄ and filtered and the filtrate was concentrated under reducedpressure to give compound 30 (0.14 g, 50%) as a brown solid.

Step Three: A solution of compound 30 (0.1 g, 0.36 mmol) and compound 8(0.082 g, 0.40 mmol) in anhydrous DMF (5 mL) was heated to 70° C.overnight. The mixture was cooled, diluted with ethyl acetate and washedwith 1N HCl (3 times) and brine. The organic layer was dried over MgSO₄and filtered and the filtrate was concentrated under reduced pressure.The residue was purified by flash chromatography (SiO₂), eluting with9:1 CHCl₃:MeOH to give compound 31 (0.17 g, 97%).

Step Four: A solution of compound 31 (0.170 g, 0.35 mmol) in THF (3 mL)was treated with 2N NaOH (1 mL). Methanol was added until a homogeneoussolution was achieved. The reaction mixture was stirred at roomtemperature for 30 minutes and poured into H₂O (50 mL). The aqueouslayer was washed with diethyl ether (twice), and then acidified with 1NHCl. The aqueous layer was extracted with ethyl acetate (twice). Thecombined ethyl acetate extracts were washed with brine (twice), driedover MgSO₄ and filtered. The filtrate was concentrated under reducedpressure to give(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (32, 0.150 g, 94%) as an off-white solid. Melting point: 113-115°C.

EXAMPLE 9 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid

Step One: Compound 33 (prepared from compound 28 according to proceduresdescribed in Example 1, 0.20 g, 0.50 mmol) was dissolved in DMF (1.8 mL)and water (0.7 mL) and treated with K₃PO₄ (0.39 g, 1.86 mmol) and phenylboronic acid (0.113 g, 0.93 mmol). The resulting mixture wasdeoxygenated (switching between vacuum and nitrogen 5 times), thentetrakis(triphenylphosine)palladium(0) (8.7 mg, 0.050 mmol) was added.The mixture was deoxygenated as before and heated at 90° C. overnight.The mixture was cooled, diluted with water and extracted with ethylacetate (2 times). The combined extracts were washed with brine, driedover MgSO₄ and filtered through silica gel and concentrated underreduced pressure. The residue was suspended in 1:1 water:concentratedHCl (2 mL) and acetonitrile (0.5 mL). The suspension was brought toreflux for 1 hour, then cooled, and partitioned between ethyl acetateand saturated aqueous NaHCO₃. The ethyl acetate layer was washed withbrine, dried over MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash chromatography (SiO₂, 3:1hexanes/ethyl acetate) to give compound 34 (0.115 g, 94%). This materialwas used without purification.

(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid was prepared from Compound 34 according procedures described inExample 1. ¹H NMR (400 MHz, CD₃OD): δ 2.25 (s, 3H), 2.50 (m, 2H), 4.89(t, J=5.9 Hz, 1H), 5.34 (s, 2H), 6.40 (d, J=7.0 Hz, 1H), 7.0 (d, J=8.0Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.18 (m, 1H), 7.28 (m, 2H), 7.35 (m,3H), 7.43 (m, 1H), 7.49 (m, 3H).

EXAMPLE 10 Synthesis of(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid (43)

Step One: Compound 35 (2.00 g 18.2 mmol) was dissolved in 30 mL of drymethanol. To this was added benzylamine (1.97 g 18.2 mmol) andtriethylamine (2.0 g 20.0 mmol). The reaction mixture was stirred at 50°C. for 3 hours, and then concentrated under reduced pressure. Theresidue was partitioned between H₂O and CH₂Cl₂. The organic layer wasdried over MgSO₄ and filtered and the filtrate was concentrated underreduced pressure to give compound 36 (2.3 g, 82%).

Step Two: To a solution of compound 37 (3.50 g, 26.5 mmol) in ethanol(10 mL) and pyridine (5 mL) was added isovaleraldehyde (2.8 mL 27 mmol)and piperidine (1 mL). The reaction mixture was heated to reflux for 3hours and concentrated under reduced pressure. The residue waspartitioned between 2N HCl (15 mL) and ethyl acetate (30 mL). Theorganic layer was dried over MgSO₄, and filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with 2:1 hexanes:ethyl acetate to givecompound 38 (3.6 g, 67%).

Step Three: A solution of compound 38 (2.5 g, 12.48 mmol) and compound36 (2.52 g, 13.7 mmol) in dry methanol (25 mL) was heated to vigorousreflux for 3 hours, cooled and concentrated under reduced pressure. Theresidue was chromatographed on silica gel eluting with 2:1hexanes:ethylacetate to give compound 39 (2.75 g, 69%).

Step Four: To a solution of compound 39 (2.5 g, 7.9 mmol) in CCl₄ (15mL) was added NBS (1.4 g, 8.0 mmoL), K₂CO₃ (11.0 g, 80.0 mmol), andbenzoyl peroxide (50 mg, 0.20 mmol). The reaction mixture was heated toreflux for 1 hour, cooled to room temperature, diluted with H₂O andextracted with CH₂Cl₂. The organic layer was dried over MgSO₄ andfiltered and the filtrate was concentrated under reduced pressure. Theresidue was chromatographed on silica gel eluting with 3:1 hexanes:ethylacetate to give compound 40 (0.62 g, 25%).

Step Five: Compound 40 (0.60 g, 1.9 mmol) was treated with 2N NaOH (5mL) and THF (3 mL). The resulting mixture was stirred at roomtemperature for 2 hours, acidified with 2N HCl and extracted with ethylacetate. The organic layer was dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure to give compound 41(560 mg, 98%).

Step Six: To a solution of compound 41 (0.56 g, 1.86 mmol) in drybenzene (10 mL), diphenylphosphorylazide (0.56 g, 2.0 mmol) andtriethylamine (2.02 g, 2.0 mmol) were added. The reaction mixture washeated to 90° C. for 1 hour then a solution of compound 8 (0.39 g, 1.9mmol) in benzene (2 mL) was added. The reaction was stirred at 90° C.for an additional 1 hour, cooled to room temperature, diluted with 10%aqueous ammonium chloride and extracted with ethyl acetate. The organiclayer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure. The residue was chromatographed onsilica gel, eluting with 7:3 ethyl acetate:hexane to give compound 42(0.38 g, 40%).

Step Seven: To a solution of compound 42 (0.35 g 0.7 mmol) in 1:1mixture of THF:MeOH (8 mL) was added 2N NaOH (8 mL). The reaction wasstirred at room temperature for 3 hours, acidified with 2N HCl (10 mL)and extracted with ethyl acetate (20 mL). The organic layer was driedover MgSO₄ and filtered and the filtrate was concentrated under reducedpressure to give(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid (43, 250 mg, 75%). MS: Calculated: (M+H)⁺=477.25 m/z. Found:(M+H)⁺=477.17 m/z.

EXAMPLE 11 Synthesis of(3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: A solution of compound 36 (2.3 g, 15.5 mmol) and compound 44(3.36 g, 15.5 mmol) in absolute ethanol (35 mL) was refluxed for 3 hoursand concentrated. The residue was chromatographed on silica gel, elutingwith 1:1 ethyl acetate:hexane to give compound 45 (1.87 g, 55% yield).

(3S)-3-[({[2-Methyl-6-oxo-1-(phenylmethyl)-1,6-dihydro-5-pyrimidinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was prepared from compound 45 according to procedures described inExample 10. ¹H NMR (400 MHz, CD₃OD) δ 2.28 (s, 3H), 2.35 (s, 3H), 2.57(m, 2H), 5.16 (m, 1H), 5.30 (s, 2H), 7.13 (m, 4H), 7.30 (m, 5H), 8.50(s, 1H).

EXAMPLE 12 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid

Step One: To a solution of compound 46 (prepared according to proceduresdescribed in Example 3, 0.50 g, 1.8 mmol) in THF (10 mL) at 0° C. wasadded NaH (60% dispersion in mineral oil, 0.23 g, 5.1 mmol). The mixturewas stirred for 10 minutes at 0° C., then ethyl isocyanate (0.65 g, 9.15mmol) was added. The mixture was stirred at room temperature over theweekend, was quenched with 1 N HCl and extracted with ethyl acetate. Theorganic layer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give compound 47 (0.60 g). Thismaterial was used without purification.

(3S)-3-{[({1-[(2-Chlorophenyl)methyl]-4-[({ethyl[(ethylamino)carbonyl]amino}carbonyl)amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid was prepared from compound 47 according to procedures described inExample 3. Melting point: 128-130° C.

EXAMPLE 13 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid

Step One: To a solution of compound 48 (2.00 g, 9.70 mmol) in anhydrousDMF (25 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 0.89g, 22 mmol). The mixture was stirred at 0° C. for 15 minutes before theaddition of 2-chlorobenzylchloride (2.03 g, 12.6 mmol). After stirringat 55° C. overnight, the mixture was poured into ice-water and washedwith Et₂O (twice). The aqueous layer was acidified and filtration of theresulting precipitate gave compound 49 (3.45 g). This material was usedwithout purification.

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3-quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid was prepared from compound 49 according to procedures described inExample 8. Melting point: 134-136° C.

EXAMPLE 14 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid (56)

Step One: To a suspension of compound 51 (1.67 g, 9.81 mmol) in DMF (33mL) at room temperature under a dry, nitrogen atmosphere,2-chlorobenzylamine (1.30 mL, 10.8 mmol) and EDCI (2.35 g, 12.3 mmol)were added sequentially. The resulting mixture was vigorously stirred atroom temperature for 5 hours, diluted with ethyl acetate and washed with2 N HCl, H₂O (3 times), saturated aqueous NaHCO₃ and brine. The organiclayer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give compound 52 (2.55 g, 100%)as a pale yellow solid.

Step Two: A solution of compound 52 (555 mg, 2.17 mmol) and3-dimethylamino-2-methylpropenal (738 mg, 6.5 mmol) in absolute ethanol(4.3 mL) and glacial acetic acid (0.22 mL) was heated to refluxovernight. The resulting mixture was cooled to room temperature, dilutedwith ethyl acetate and washed with 2 N HCl (twice), H₂O and brine. Theorganic layer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure. The pressure was purified bychromatography on silica gel, eluting with 7:3 increasing to 1:1hexanes:ethyl acetate and finally 19:19:2 hexanes:ethyl acetate:methanolto yield compound 53 (182 mg, 27%) as a yellow oil.

Step Three: To a solution of compound 53 (167 mg, 0.55 mmol) in THF (3mL), 2 N NaOH (1 mL) and methanol (2 mL) were added. The resultingmixture was stirred for 15 minutes, diluted with H₂O and extracted withethyl ether. The aqueous layer was acidified with 2 N HCl and extractedwith ethyl acetate. The ethyl acetate layer was washed with H₂O andbrine, dried over MgSO₄ and filtered. The filtrate was concentratedunder reduced pressure to give compound 54 (139 mg, 91%) as a whitesolid.

Step Four: To a suspension of compound 54 (175 mg, 0.63 mmol) in THF(6.7 mL) and DIPEA (0.23 mL, 1.34 mmol) at room temperature under a dry,nitrogen atmosphere, DPPA (0.29 mL, 1.34 mmol) was added via syringe.The resulting mixture was stirred at room temperature for 15 minutes,then heated to reflux for 3.5 hours. The mixture was allowed to cool toroom temperature and a solution of compound 8 (278 mg, 1.34 mmol) in THF(6.0 mL) was added via cannula along with a THF (0.7 mL) rinse. Theresulting mixture was stirred at room temperature overnight, dilutedwith ethyl acetate and washed with 2 N HCl (twice), saturated aqueousNaHCO₃ and brine. The organic layer was dried over MgSO₄ and filteredand the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel chromatography, eluting with 7:3 then 3:2 andfinally 1:1 hexanes:ethyl acetate to yield compound 55 (60 mg, 20%) as acolorless oil.

Step Five: To a solution of compound 55 (60 mg, 0.12 mmol) in THF (3mL), 0.192 N NaOH (0.65 mL, 0.12 mmol) and methanol (2 mL) were added.The resulting mixture was stirred at room temperature for 24 hours, thenwas diluted with H₂O. The organic solvents were removed under reducedpressure and the resulting aqueous mixture was extracted with ethylether. The aqueous phase was lyophilized to give(3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid, sodium salt (56, 56 mg, 95%) as an off-white solid. MS: Calculatedfor (C₂₄H₂₃CIN₃O₄)⁻: 452.14 m/z. Found: 451.99 m/z.

EXAMPLE 15 Synthesis of(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(2-thienylmethyl)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propanoicacid (62)

Step One: To a solution of 2-thiophenemethanol (1.015 g, 8.89 mmol) inCH₂Cl₂ (17.8 ml) cooled to 0° C. under a dry nitrogen atmosphere,triethylamine (2.98 ml, 21.4 mmol) and methanesulfonyl chloride (0.69ml, 8.9 mmol) were added sequentially by syringe. The resulting mixturewas stirred at 0° C. for 15 minutes, then 2-hydroxy-3-nitropyridine(1.496 g, 10.7 mmol) and 4-dimethylaminopyridine (catalytic) were added.The mixture was allowed to gradually warm to room temperature and thenwas stirred overnight. The mixture was diluted with ethyl acetate andwashed with 2N HCl, H₂O, saturated NaHCO₃ and brine. The organic phasewas dried over MgSO4 and filtered and the filtrate was concentratedunder reduced pressure to give 58 (395 mg) as a yellow waxy solid. Thismaterial was used without purification.

Step Two: To a solution of 58 (330 mg, 1.40 mmol) in glacial acetic acid(6.6 ml) at room temperature under a dry nitrogen atmosphere, ironpowder (154 mg, 2.8 mmol, −325 mesh) was added. The resulting solutionwas heated to 60° C. in an oil bath with vigorous stirring for 20minutes. The mixture was cooled to room temperature, diluted with ethylacetate and filtered through Celite. The filtrate was washed with H₂O,saturated NaHCO₃ and brine. The organic phase was dried over MgSO₄ andfiltered and the filtrate was concentrated under reduced pressure. Theresidue was filtered through silica gel, eluting with 1:1 hexanes:ethylacetate increasing to 1:3 hexanes:ethyl acetate to yield 59 (188 mg, 12%for two steps) as a greenish solid.

Step Three: To a solution of 59 (111 mg, 0.54 mmol) in CH₂Cl₂ (2.7 ml)cooled to 0° C. under a dry nitrogen atmosphere,N,N-diisopropylethylamine (0.23 ml, 1.30 mmol) and phosgene (0.31 ml,1.9M in toluene, 0.59 mmol) were added sequentially by syringe. Theresulting mixture was stirred at 0° C. for 15 minutes, then a solutionof β-amino ester 60 (167 mg, 0.70 mmol) in CH₂Cl₂ (2.7 ml) was added bycannula along with a CH₂Cl₂ rinse (1.0 ml). The resulting mixture wasallowed to warm to room temperature, was stirred for 2 hours, wasdiluted with ethyl acetate and washed with 2N HCl, H₂O, saturated NaHCO₃and brine. The organic phase was dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with 1:1 hexanes:ethylacetate to yield 61 (231 mg, 91%) as a purple foam.

Step Four: To a solution of ester 61 (227 mg, 0.48 mmol) in THF (6 ml)at room temperature, NaOH (2 ml, 2N in H₂O, 4 mmol) and methanol (enoughto give a clear solution, approximately 2 ml) were added. The resultingmixture was stirred for 15 minutes, then was diluted with water andextracted with ether. The aqueous phase was acidified with HCl (2N) andextracted with ethyl acetate. The organic phase was washed with brine,dried over MgSO₄ and filtered and the filtrate was concentrated underreduced pressure to give 62 (191 mg, 90%) as a white solid. ¹H NMR (400MHz, CD₃SOCD₃) δ 2.63 (d, J=7.3 Hz, 2H), 4.99 (dt, J=8.4, 7.3 Hz, 1H),5.30 (s, 2H), 5.98 (m, 2H), 6.21 (dd, J=7.5, 7.0 Hz, 1H), 6.78 (dd,J=8.1, 1.6 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.88 (d, J=1.6 Hz, 1H), 6.97(dd, J=5.1, 3.5 Hz, 1H), 7.17 (dd, J=3.5, 1.1 Hz, 1H), 7.35 (dd, J=7.0,1.8 Hz, 1H), 7.44 (dd, J=5.1, 1.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.94(dd, J=7.5, 1.8 Hz, 1H), 8.40 (s, 1H).

EXAMPLE 16 Synthesis of(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienylmethyl)hexahydro-3-pyridinyl]amino}carbonyl)amino]propanoicacid (68)

Step One: To a solution ofN-α-tert-butoxycarbonyl-N-δ-benzyloxycarbonyl-L-omithine 63 (1.00 g,2.73 mmol) and cesium carbonate (1.33 g, 4.1 mmol) in DMF (10 ml) atroom temperature under a dry nitrogen atmosphere, iodomethane (0.22 ml,3.3 mmol) was added by syringe. The resulting mixture was stirred atroom temperature for 18 hours then was diluted with ethyl acetate andwashed with H₂O, 10% Na₂S₂O₅, saturated NaHCO₃ and brine. The organicphase was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give ester 64 (1.21 g) as a paleyellow oil. This material contained DMF but was used withoutpurification.

Step Two: To a solution of 64 (0.86 g of crude material prepared inprevious procedure, 1.94 mmol theoretical) in methanol (10 ml) at 0° C.under a dry nitrogen atmosphere, palladium on charcoal (300 mg, 10% Pd,Degussa type E101 NE/W, wet, 50% water by weight) was added. Thenitrogen atmosphere was replaced by hydrogen (alternate five timesbetween vacuum and hydrogen supplied by balloon) and the mixture wasstirred at 0° C. for 30 minutes then filtered directly into a flaskcontaining 2-thiophenecarboxaldehyde (177 mg, 1.58 mmol). The mixturewas concentrated (water bath at room temperature) and the residue wastaken up in dichloroethane (6 ml). To this solution, sodiumtriacetoxyborohydride (479 mg, 2.26 mmol) was added and the mixture wasstirred for 2 hours, diluted with ethyl acetate and washed withsaturated NaHCO₃ (2 times) and brine. The organic phase was dried overMgSO₄ and filtered and the filtrate was concentrated under reducedpressure. The residue was filtered through silica gel, eluting with 7:3hexanes:ethyl acetate to yield lactam 65 (75 mg, 12% for two steps) as acolorless oil.

Step Three: To a flask containing 65 (89 mg, 0.29 mmol) sealed with arubber septum at room temperature under a dry nitrogen atmosphere, HCl(7.2 ml, 4.0M in dioxane, 28.8 mmol) was added by syringe. The nitrogenneedle was removed and the mixture in the sealed flask was stirredovernight. The mixture was diluted with CH₂Cl₂ and washed with saturatedNaHCO₃. The organic phase was dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure to give amine 66 (60mg, 100%) as a light yellow oil. This material was used withoutpurification.

Step Four: To a solution of β-amino ester 60 (75 mg, 0.32 mmol) inCH₂Cl₂ (0.6 ml) at room temperature under a dry nitrogen atmosphere,carbonyldiimidazole (51 mg, 0.32 mmol) was added. The resulting mixturewas stirred at room temperature for 5 minutes and a solution of amine 66(60 mg, 0.29 mmol) in CH₂Cl₂ (0.6 ml) was added by cannula along with aCH₂Cl₂ (0.2 ml) rinse. The resulting mixture was stirred at roomtemperature for 3 days, then was diluted with ethyl acetate and washedwith 2N HCl (2 times), H₂O, saturated NaHCO₃ and brine. The organicphase was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure. The residue was filtered throughsilica gel, eluting with 1:1 hexanes:ethyl acetate increasing to 2:3hexanes:ethyl acetate to yield urea 67 (110 mg, 80%).

Step Five: To a solution of urea 67 (108 mg, 0.23 mmol) in THF (3 ml) atroom temperature, NaOH (1 ml, 2N in H₂O, 2 mmol) and methanol (enough togive a clear solution, approximately 2 ml) were added. The resultingmixture was stirred for 15 minutes, then was diluted with water andextracted with ether. The aqueous phase was acidified with HCl (2N) andextracted with ethyl acetate. The ethyl acetate layer was washed withbrine, dried over MgSO₄ and filtered and the filtrate was concentratedunder reduced pressure to give 68 (92 mg, 90%) as a white foam. ¹H NMR(400 MHz, CD₃SOCD₃) δ 1.45 (m, 1H), 1.76 (m, 2H), 2.62 (m, 2H), 3.25 (moverlapping H₂O, 2H), 4.01 (m, 1H), 4.59 (d, J=15.0 Hz, 1H), 4.68 (d,J=15.0 Hz, 1H), 4.96 (m, 1H), 5.97 (s, 2H), 6.24 (d, J=6.6 Hz, 1H), 6.71(d, J=8.4 Hz, 1H), 6.75 (dd, J=8.1, 1.5 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H),6.85 (d, J=1.5 Hz, 1H), 6.97 (dd, J=5.1, 3.3 Hz, 1H), 7.03 (dd, J=3.3,1.5 Hz, 1H), 7.42 (dd, J=5.1, 1.5 Hz, 1H), 12.06 (br. s, 1H).

EXAMPLE 17 Synthesis of(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2-thienylmethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propanoicacid (74)

Step One: To a solution of N-tert-butoxycarbonyl-L-aspartic acidα-benzylester (2.10 g, 6.5 mmol) in dimethoxyethane (15 ml) cooled to−15° C. (bath temperature) under a dry nitrogen atmosphere,4-methylmorpholine (0.71 ml, 6.5 mmol) and isobutyl chloroformate (0.84ml, 6.5 mmol) were added sequentially by syringe. The resulting mixturewas stirred for 2 minutes, then was filtered, washing the solid cakewith dimethoxyethane (10 ml). The filtrate was recooled to −15° C. (bathtemperature) and a solution of sodium borohydride (370 mg, 9.7 mmol) inH₂O (3 ml) was added followed immediately by the addition of H₂O (100ml). The mixture was extracted with ethyl acetate (3 times) and theorganic layers were combined and washed with cold (0° C.) HCl (0.2N),H₂O, saturated NaHCO₃ and brine. The resulting organic layer was driedover MgSO₄ and filtered and the filtrate was concentrated under reducedpressure to give 69 (2.50 g) as a colorless oil. This material containssome of the unreduced mixed-anhydride but was used without purification.

Step Two: To a solution of oxalyl chloride (2.4 ml, 2.0 M in CH₂Cl₂, 4.8mmol) in CH₂Cl₂ (30 ml) cooled to −65° C. under a dry nitrogenatmosphere, a solution of methylsulfoxide (0.55 ml, 7.8 mmol) in CH₂Cl₂(8 ml) was added by syringe. The resulting mixture was stirred at −65°C. for 15 minutes, then a solution of alcohol 69 (1.00 g, 3.2 mmol) inCH₂Cl₂ (29 ml) was added by cannula along with a CH₂Cl₂ (3 ml) rinse.The mixture was stirred at −65° C. for 3 hours, then was allowed to warmto −20° C. (bath temperature). Triethylamine (0.96 ml, 6.9 mmol) wasadded, followed by H₂O (20 ml). The aqueous layer was extracted withCH₂Cl₂ and the combined organic phases were dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure to givealdehyde 70 as a white solid. This material was used immediately withoutpurification.

Step Three: To a solution of the crude aldehyde 70 (3.2 mmoltheoretical) and 2-aminomethylthiophene (402 mg, 3.55 mmol) indichloroethane (13 ml) at room temperature under a dry nitrogenatmosphere, sodium triacetoxyborohydride (959 mg, 4.5 mmol) was added.The resulting mixture was stirred at room temperature overnight, thenwas diluted with ethyl acetate and washed with saturated NaHCO₃ andbrine. The organic phase was dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with 1:1 hexanes:ethylacetate to yield lactam 71 (220 mg, 23% for 3 steps) as a white solid.

Step Four: To a solution of 71 (220 mg, 0.74 mmol) in dioxane (1.5 ml)sealed with a rubber septum at room temperature under a dry nitrogenatmosphere, HCl (1.50 ml, 4.0M in dioxane, 6.0 mmol) was added bysyringe. The nitrogen needle was removed and the mixture in the sealedflask was stirred for 5 hours. The mixture was diluted with CH₂Cl₂ andwashed with saturated NaHCO₃. The organic phase was dried over MgSO₄ andfiltered and the filtrate was concentrated under reduced pressure togive amine 72 (129 mg, 89%) as a light yellow oil. This material wasused without purification.

Step Five: To a solution of amine 72 (123 mg, 0.63 mmol) in CH₂Cl₂ (1.5ml) at room temperature under a dry nitrogen atmosphere,carbonyldiimidazole (112 mg, 0.69 mmol) was added. The resulting mixturewas stirred at room temperature for 5 minutes and a solution of aminoester 60 (164 mg, 0.69 mmol) in CH₂Cl₂ (0.8 ml) was added by cannulaalong with a CH₂Cl₂ (0.2 ml) rinse. The resulting mixture was stirred atroom temperature overnight, then was diluted with ethyl acetate andwashed with 2N HCl (2 times), H₂O, saturated NaHCO₃ and brine. Theorganic phase was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure. The residue was filtered throughsilica gel, eluting with 49:1 chloroform:methanol to yield urea 73 (230mg, 80%) as a colorless oil which slowly solidified on standing.

Step Six: To a solution of urea 73 (230 mg, 0.50 mmol) in THF (3 ml) atroom temperature, NaOH (1 ml, 2N in H₂O, 2 mmol) and methanol (1 ml)were added. The resulting mixture was stirred for 1 hour, then wasdiluted with water and extracted with ether. The aqueous phase wasacidified with HCl (2N) and extracted with ethyl acetate. The ethylacetate layer was washed with brine, dried over MgSO₄ and filtered andthe filtrate was concentrated under reduced pressure to give 74 (181 mg,84%) as a white foam. ¹H NMR (400 MHz, CD₃SOCD₃) δ 1.64 (m, 1H), 2.30(m, 1H), 2.64 (m, 2H), 3.20 (m, 2H), 4.17 (dd, J=8.8, 8.4 Hz, 1H), 4.56(s, 2H), 4.96 (m, 1H), 5.97 (s, 2H), 6.30 (d, J=7.0 Hz, 1H), 6.58 (d,J=8.8 Hz, 1H), 6.77 (m, 1H), 6.80-6.90 (m, 2H), 6.96-7.04 (m, 2H), 7.45(dd, J=5.1, 0.7 Hz, 1H), 12.10 (br. s, 1H).

EXAMPLE 18 Synthesis of(3S)-3-[({[5-chloro-2-hydroxy-3-(phenylmethyl)phenyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: To a mixture of 2-phenylmethyl-3-chlorophenol (5.00 g, 22.9mmol) in Et₂O (20 mL) and 6N HCl (50 mL), KNO₃ (2.30 g, 22.9 mmol) andNaNO₂ (20 mg, catalytic) were added sequentially. The resulting mixturewas stirred for 2 hours, diluted with water and extracted with ethylacetate. The organic layer was washed with water and brine, dried overMgSO₄ and filtered. The filtrate was concentrated under reduced pressureto give 99 (6.0 g, 100%).

Step Two: To a solution of 99 (6.0 g, 22.8 mmol) in methanol (360 mL),zinc powder (6.0 g, 92 mmol) and saturated aqueous NH₄Cl (6 mL) wereadded. The resulting heterogeneous mixture was refluxed overnight. Afterfiltration of the hot mixture and concentration of the filtrate underreduced pressure, the residue was dissolved in ethyl acetate and washedwith saturated aqueous NaHCO₃ and brine. The organic layer was driedover MgSO₄ and filtered and the filtrate was concentrated under reducedpressure to give compound 100 (2.93 g, 55%).

Step Three: To a solution of 25 (0.20 g, 0.96 mmol) in CH₂Cl₂ at 0° C.,DIPEA (0.40 mL, 2.4 mmol) and phosgene (1.93 M in toluene, 0.60 mL, 1.2mmol) were added sequentially. The resulting mixture was allowed to warmto room temperature, stirred for 20 minutes, then recooled to 0° C. Tothis mixture, a solution of 100 (0.25 g, 1.1 mmol) in CH₂Cl₂ was addeddropwise. The resulting mixture was allowed to warm to room temperatureovernight, was diluted with water and was extracted with CH₂Cl₂. Theorganic layer was washed with water and brine, dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by silica gel chromatography, eluting with 9:1 andincreasing to 5:1 hexanes:ethyl acetate to give 101 (60 mg, 12%).(3S)-3-[({[5-Chloro-2-hydroxy-3-(phenylmethyl)phenyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was prepared from 101 by procedures described in Example 1. ¹H NMR(400 MHz, CD₃SO₂CD₃) δ 2.26 (s, 3H), 2.58 (dd, J=15.8, 6.6 Hz, 1H), 2.67(dd, J=15.8, 8.4 Hz, 1H), 3.49 (s, 2H), 4.88 (m, 1H), 7.00-7.70 (m,13H), 11.95 (br. s, 1H).

EXAMPLE 19 Synthesis of(3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2,5-dioxo-1-(phenylmethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propanoicacid

Step One: A solution of N-benzylmaleimide (2.60 g, 13.9 mmol) andn-butylamine (1.00 g, 13.7 mmol) in THF (15 mL) was stirred at roomtemperature overnight and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with 4:1increasing to 2:1 hexanes:ethyl acetate to give 102 (3.25 g, 90%).

(3S)-3-(1,3-Benzodioxol-5-yl)-3-[({butyl[2,5-dioxo-1-(phenylmethyl)tetrahydro-1H-pyrrol-3-yl]amino}carbonyl)amino]propanoicacid was prepared from 102 according to procedures described inExample 1. MP: 80-85° C.

EXAMPLE 20 Synthesis of(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[1-(cyclopentylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propanoicacid

Step One: To a solution of 2-hydroxy-3-nitropyridine (200 mg, 1.4 mmol)in CH₂Cl₂ (14 mL) at 0° C. under a nitrogen atmosphere,cyclopentanemethanol (178 mg, 1.78 mmol) was added followed bytriphenylphosphine (551 mg, 2.1 mmol). The solution was stirred at 0° C.for 15 minutes and diethyl azodicarboxylate (366 mg, 2.1 mmol) was addeddropwise via syringe. The reaction was allowed to stir at 0° C. for onehour and then at room temperature overnight. The mixture was quenchedwith methanol (20 mL) and washed with water (twice). The aqueous layerwas extracted with dichloromethane and the combined organic layers weredried over magnesium sulfate and filtered. The filtrate was concentratedand the residue was purified by silica gel chromatography, eluting with1:1 hexanes:ethyl acetate to afford 103 (299 mg, 96% yield) as a yellowsolid.

(3S)-3-(1,3-Benzodioxol-5-yl)-3-[({[1-(cyclopentylmethyl)-2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propanoicacid was prepared from 103 according to procedures described inExample 1. ¹H NMR (400 MHz, CDCl₃): δ 1.2-1.7 (m, 8H), 2.34 (m, 1H),2.81 (dd, J=, 1H), 2.95 (dd, J=, 1H), 3.92 (d, J=7.7 Hz, 2H), 5.30 (m,1H), 5.92 (m, 2H), 6.30 (t, J=7.1 Hz, 1H), 6.68-7.00 (m, 5H), 8.33 (d,J=7.7 Hz, 1H), 8.89 (s, 1H).

EXAMPLE 21 Synthesis of(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({3-[(2-thiophenylmethyl)amino]phenyl}amino)carbonyl]amino}propanoicacid

Step One: To a solution of 2-thiophenecarboxaldehyde (0.48 g, 4.0 mmol)in dichloromethane was added 3-nitroaniline (0.51 g, 3.7 mmol). Thesolution was concentrated to dryness and brought up in1,2-dichloroethane (16 mL). Molecular sieves (3 Å, 1.1 g) were addedfollowed by NaBH(OAc)₃ (1.01 g, 4.8 mmol). The solution was stirredovernight at room temperature, diluted with chloroform and washed withwater. The organic layer was dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure to give 104 (0.72 g,84%).

Step Two: To a solution of 104 (0.30 g, 1.3 mmol) in CH₂Cl₂ (5.2 mL) andtriethylamine (0.215 mL, 1.5 mmol) at 0° C. was added trifluoroaceticanhydride (0.193 mL, 1.4 mmol). The solution was stirred 15 minutes at0° C., the ice bath was removed and the mixture was stirred for anadditional 15 minutes. The mixture was diluted with CH₂Cl₂, washed with2N HCl, water and brine. The organic layer was dried over Na₂SO₄ andfiltered and the filtrate was concentrated under reduced pressure togive 105 (0.38 g, 100%) as a yellow solid.

Step Three: To a solution of 105 (0.38 g, 1.4 mmol) in ethanol (2.6 mL)and acetic acid (2.6 mL) at room temperature, Fe powder (0.36 g, 6.5mmol) was added and the suspension was stirred vigorously at 40° C.until TLC indicated complete consumption of 105. The mixture wasfiltered through Celite, washing with chloroform. The filtrate wasdiltuted with saturated sodium bicarbonate and the chloroform layer wasdried over Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography onsilica gel (gradient elution 6:1 to 4:1 hexanes:ethyl acetate) to givecompound 106 (0.102 g, 25%)

(3S)-3-(1,3-Benzodioxol-5-yl)-3-{[({3-[(2-thiophenylmethyl)amino]phenyl}amino)carbonyl]amino}propanoicacid was prepared from 106 according to procedures described inExample 1. ¹H NMR (400 MHz, CD₃SO₂CD₃) δ 2.50 (m, 2H overlapping DMSO),4.37 (d, J=5.9 Hz, 2H), 4.94 (m, 1H), 5.94 (m, 2H), 6.06 (t, J=5.8 Hz,1H), 6.16 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.78 (m, 3H), 6.85 (dd,J=8.8, 7.7 Hz, 1H), 6.90 (s, 1H), 6.94 (dd, J=5.2, 3.7 Hz, 1H), 7.00 (d,J=3.3 Hz, 1H), 7.33 (dd, J=5.1, 1.1 Hz, 1H), 8.5 (s, 1H).

EXAMPLE 22 Synthesis of3-(1,3-benzodioxol-5-yl)-2,2-difluoro-3-[({[2-oxo-1-(2-thiophenylmethyl)1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propanoicacid

Step One: To a solution of (1S,2R,5S)-(+)-menthyl (R)-p-toluenesulfinate(3.00 g, 10.2 mmol) in THF (25.5 mL) chilled to −78° C., lithiumbis(trimethylsilyl)amide (1.0 M in THF, 15.3 mL) was added dropwise over15 minutes. The resulting mixture was stirred at room temperature for 6hours, then chilled to 0° C. Piperonal (3.06 g, 20.4 mmol) and CsF (3.10g, 20.4 mmol) were added rapidly and the suspension stirred 36 hours atroom temperature. The reaction was quenched with saturated NH₄Cl andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and filtered and the filtrate was concentrated underreduced pressure. The residue was recrystallized from hexanes anddichloromethane to give compound 108 (1.36 g, 46%)

Step Two: Ethyl bromodifluoroacetate (0.78 mL, 6.1 mmol) was added to asuspension of Zn dust (2.00 g, 30.5 mmol) in THF (20.2 mL) and refluxedfor 15 minutes. The suspension was chilled to 0° C. and 108 (0.87 g, 3.0mmol) was added. The suspension was allowed to warm to room temperatureand stirred overnight. The mixture was quenched with a minimum amount ofsaturated NH₄Cl and extracted with ethyl acetate. The organic layer waswashed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by chromatography on silica gel (gradient elution6:1 to 4:1 hexanes:ethyl acetate to give 109 (0.607 g, 61% at 80%conversion).

Step Three: To a solution of 109 (0.700 g, 1.70 mmol) in methanol (4.3mL) at 0° C., trifluoroacetic acid (0.26 mL 3.4 mmol) was added. Thesolution was stirred at 0° C. for 2 hours, then concentrated to drynessunder reduced pressure, while maintaining the external temperature below30° C. The residue was taken up in diethyl ether and washed with 2N HCl(2 times). The combined aqueous layers were carefully basified withexcess saturated NaHCO₃ and extracted with diethyl ether. The etherlayer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give 110 (0.326 g, 80%).

3-(1,3-Benzodioxol-5-yl)-2,2-difluoro-3-[({[2-oxo-1-(2-thiophenylmethyl)-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]propanoicacid was prepared from 110 according to procedures described inExample 1. MS: Calculated (M−H)⁻=476.07; Found (M−H)⁻=476.00.

EXAMPLE 23 Synthesis of(3S)-3-(1,3-benzodioxol-5-yl)-3-({[9-oxo-8-(phenylmethyl)-2,3,4,5,8,9-hexahydro-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propanoicacid

Step One: To a solution of 3 (0.74 g, 3.6 mmol) in THF (14.4 mL) andTMEDA (1.60 mL, 10.8 mmol) at −20° C., n-butyllithium (1.6 M in hexanes,3.4 mL, 5.4 mmol) and tert-butyllithium (1.7M in pentane, 2.5 mL, 4.3mmol) were sequentially added dropwise by syringe. The temperature wasallowed to warm to between −10 and 0° C. and maintained there for 2hours. To the resulting mixture, 1,4-dibromobutane (1.75 mL, 14.7 mmol)was added rapidly and the solution was allowed to warm to roomtemperature and stirred for 4 days. The reaction was quenched with waterand extracted with CHCl₃ (3 times). The combined extracts were washedwith brine, dried over NaSO₄ and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified by chromatography onsilica gel, eluting with 4:1 hexanes:ethyl acetate to give 111 (0.41 g,44%).

(3S)-3-(1,3-Benzodioxol-5-yl)-3-({[9-oxo-8-(phenylmethyl)-2,3,4,5,8,9-hexahydro-1H-pyrido[3,4-b]azepin-1-yl]carbonyl}amino)propanoicacid was prepared from 111 according to the procedures described inExample 4. MS: Calculated (M−H)⁻=488.18; Found (M−H)⁻=488.21.

EXAMPLE 24 Synthesis of(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-hydroxyphenyl)propanoicacid

Step One: To a solution of 112 (prepared according to proceduresdescribed in Example 15, 0.19 g, 0.39 mmol) in CH₂Cl₂ at 0° C. undernitrogen, BBr₃ (1.0 M in CH₂Cl₂, 1.2 mL, 1.2 mmol) was added by syringe.The mixture was allowed to gradually warm to room temperature and thenstirred overnight. The mixture was diluted with water and stirred for 30minutes and further diluted with saturated aqueous NaHCO₃. The organiclayer was washed with water and the aqueous layers were combined andacidified with 2N HCl and extracted with ethyl acetate (3 times). Thecombined ethyl acetate layers were dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure to yield(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-hydroxyphenyl)propanoicacid (113, 120 mg, 70%). ¹H NMR (400 MHz, CD₃SO₂CD₃) δ 2.95 (d, J=5.2Hz, 2H), 5.28 (s, 2H), 5.35 (ddd, J=9.2, 4.8, 4.4 Hz, 1H), 6.33 (t,J=7.1 Hz, 1H), 6.60 (d, J=8.8 Hz, 2H), 7.04 (m, 5H), 7.22 (m, 3H), 7.37(dd, J=7.7, 1.5 Hz, 1H), 8.35 (dd, J=7.6, 1.5 Hz, 1H), 8.80 (s, 1H).

EXAMPLE 25 Synthesis of(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid, 119

Step One: To a suspension of sodium hydride (3.6 g of 60% dispersion inmineral oil, 90 mmol) in THF (300 mL) under a dry nitrogen atmosphere,TMEDA (13.2 mL, 87.5 mmol) was added and the mixture was cooled to −20°C. Methyl propionylacetate (9.60 mL, 76.5 mmol) was added dropwise andthe solution was stirred for an additional 15 minutes. A solution ofn-butyllithium (90 mL, 1.6M in hexanes, 144 mmol) was added dropwise andthe resulting mixture was stirred at −20° C. for 15 minutes. Methylformate (6.0 mL, 97 mmol) was then added rapidly and the mixture wasallowed to stir for 15 minutes before quenching with HCl (2 N, 250 mL).The reaction was diluted with diethyl ether (150 mL) and the organiclayer was washed twice more with water. The aqueous layers were combinedand sodium chloride was added until saturated. This mixture wasextracted with ethyl acetate (3 times). The original ether layer waswashed with saturated sodium bicarbonate solution and water. Thecombined aqueous washes were acidified with excess HCl (2 N), saturatedwith sodium chloride and extracted with ethyl acetate (3 times). All ofthe ethyl acetate extracts were combined and dried over MgSO₄. Theresulting mixture was vacuum filtered through coarse silica gel and thefiltrate was concentrated under reduced pressure to give 114 (8.27 g,68%) as a light yellow oil. This material was used without furtherpurification.

Step Two: To a solution of 114 (3.95 g, 25.0 mmol) in anhydrous methanol(225 mL) at room temperature, a solution of 2-chlorobenzylamine (4.2 g,30 mmol) in anhydrous methanol (25 mL) was added dropwise from anaddition funnel. The solution was heated at 45° C. overnight thenrefluxed for two hours. The reaction mixture was cooled to roomtemperature and concentrated to dryness. The residue was brought up indichloromethane and filtered. The solid was collected and dried undervacuum to give 115 (2.20 g 35%) as a light yellow solid.

Step Three: To a suspension of 115 (840 mg, 3.4 mmol) in glacial aceticacid (11 mL) at room temperature, NaNO₂ (46 mg, 0.67 mmol), water (0.92mL) and HNO3 (70%, 0.85 mL, 13.4 mmol) were added sequentially. Theresulting bright yellow solution was stirred at room temperatureovernight, then was diluted with CH₂Cl₂ and water. The aqueous phase wasextracted with CH₂Cl₂, the organic layers were combined and washed withwater (3 times) and brine. The organic layer was dried over MgSO₄ andfiltered and the filtrate was concentrated under reduced pressure togive 116 (910 mg, 92%) as a bright yellow solid. This material was usedwithout purification.

Step Four: To a solution of 116 (910 mg, 3.1 mmol) in DMF (10.3 mL) atroom temperature under a dry nitrogen atmosphere, Zn powder (909 mg,13.9 mmol) and triethylamine hydrochloride (2340 mg, 17.0 mmol) wereadded. The resulting mixture was heated to 55° C. for 2 hours, then wascooled to room temperature. To the resulting mixture, CDI (1002 mg, 6.18mmol) was added as a solid. Upon addition, gas evolution occurred. Themixture was then heated to 80° C. for 1 hour, cooled to roomtemperature, and diluted with CH₂Cl₂ and HCl (2 N). The aqueous phasewas extracted with CH₂Cl₂, the organic layers were combined and washedwith water (4 times) and brine. The organic layer was dried over MgSO₄and filtered and the filtrate was concentrated under reduced pressure togive 117 (920 mg) as a yellow solid. This material contained a smallamount of DMF and was used without purification.

Step Five: A suspension of 117 (920 mg crude material, 3.1 mmoltheoretical) and 8 (800 mg, 3.86 mmol) in 21 ml THF under a dry nitrogenatmosphere was heated to 55° C. overnight, cooled to room temperatureand then diluted with ethyl acetate. The resulting mixture was washedtwice with HCl (2N) and brine and the organic layer was dried over MgSO₄and filtered. The filtrate was concentrated under reduced pressure andthe resulting residue was purified by silica gel chromatography, elutingwith 7:3 hexanes:ethyl acetate to give 118 (1098 mg, 71% for two steps)as a pale yellow foam.

Step Six: To a solution of 118 (1091 mg, 2.19 mmol) in THF (18 mL) aroom temperature sodium hydroxide (2 N, 6 ml) and methanol (12 mL) wereadded. The mixture was stirred for 20 minutes, then was diluted withwater and extracted with ethyl ether. The aqueous phase was acidifiedwith HCl (2 N) and extracted with ethyl acetate. The ethyl acetate layerwas washed with water and brine, dried over MgSO₄ and filtered. Thefiltrate was concentrated under reduced pressure to give(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid, 119, (1045mg, quantitative) as a white foam. MS: Calculated (M−H)⁻=468.13 m/z.Found (M−H)⁻=467.99 m/z.

EXAMPLE 26 Synthesis of(3S)-3-[({[4-hydroxy-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: To a solution of 23 (0.50 g, 3.2 mmol) in DMSO (12.5 ml) atroom temperature, powdered KOH (0.89 g, 16 mmol) was added and themixture was stirred for 1.5 hours. To the resulting mixture,2-picolylchloride hydrochloride (0.63 g, 3.8 mmol) was added as a solidand the mixture was stirred overnight. At this point, triethylaminehydrochloride (3.52 g, 25.6 mmol) and DMF (5 mL) were added followed byzinc powder (1.04 g, 16.0 mmol). The mixture was heated to 80° C. for 2hours then cooled to room temperature. To this mixture, CDI (1.00 g, 6.2mmol) was added and the resulting mixture was heated to 80° C.overnight. The mixture was diluted with ethyl acetate and saturatedaqueous NaHCO₃. The organic layer was dried over MgSO₄ and filtered andthe filtrate was concentrated under reduced pressure. The residue wasfiltered through a pad of silica gel, eluting with 9:1 CHCl₃:CH₃OH togive 120 (0.14 g, 18%).

(3S)-3-[({[4-Hydroxy-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was prepared from 120 according to procedures described in Example25. MS: Calculated (M−H)⁻=421.15 m/z. Found (M−H)⁻=421.06 m/z.

EXAMPLE 27 Synthesis of(3S)-3-{[({1-[2-chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid

Step One: To a solution of 121 (prepared from 23 according to proceduresdescribed in Example 4, 220 mg, 0.67 mmol) in anhydrous CH₂Cl₂ (14 mL)cooled to 0° C. under a dry, nitrogen atmosphere, m-CPBA (610 mg, 3.6mmol) was added. The resulting mixture was allowed to warm to roomtemperature and stirred for 4 hours. The reaction was diluted with water(50 ml) and the aqueous phase was extracted with CH₂Cl₂ (2 times). Thecombined organic layers were dried over MgSO₄ and filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with 9:1 CHCl₃:MeOH togive 122 (219 mg, 91% yield) as a yellow solid.

(3S)-3-{[({1-[2-Chloro-5-(methylsulfonyl)benzyl]-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid was prepared from 122 according to procedures described in Example25. MS: Calculated (M−H)⁻=532.10 m/z. Found (M−H)⁻=531.94 m/z.

EXAMPLE 28 Synthesis of(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoicacid

Step One: To a solution of the 123 (70 mg, 0.13 mmol) in anhydrousCH₂Cl₂ (3 mL), stirring under a nitrogen atmosphere, ZnBr₂ (200 mg, 0.82mmol) was added. The solution was stirred at 0° C. for one hour. Thereaction mixture was allowed to warm to room temperature and was stirredovernight. At this point, water (50 ml) was added and the mixture wasstirred for an additional three hours. The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (2 times). The combined organiclayers were dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoicacid, 124 (60 mg, 95% yield). MS: Calculated (M−H)⁻=484.13 m/z. Found(M−H)⁻=484.00 m/z.

EXAMPLE 29 Synthesis of(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: A mixture of malonyl dichloride (25.0 g, 177 mmol) andvaleronitrile (25.0 g, 300.7 mmol) under an anhydrous atmosphere wasvigorously stirred at room temperature for 24 hours. Diethyl ether (50mL) was added to the resulting heterogeneous mixture. The precipitatewas collected and washed with diethyl ether to give 125.HCl as a whitesolid (20.2 g, 64%).

Step Two: To a suspension of 125.HCl (6.10 g, 27.2 mmol) in EtOH (100mL), triethylamine (5.8 g, 57.3 mmol) and palladium on carbon (10% Pddry weight basis, Degussa type E101 NE/W, ˜50% water content, 3.5 g, 1.6mmol Pd) were added. The atmosphere was replaced with hydrogen (togglebetween vacuum and hydrogen from a balloon five times) and the mixturewas stirred overnight, then filtered. The filtrate was concentratedunder reduced pressure to give 126.2Et₃NHCl (11.0 g, 94%). This materialwas used without further purification.

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was prepared from 126.2Et₃NHCl according to procedures described inExample 25. MS: Calculated (M−H)⁻=496.16 m/z. Found (M−H)⁻=495.94 m/z.

EXAMPLE 30 Synthesis of(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: To a solution of ethyl 2-oxocyclopentanecarboxylate (3.30 g,21.1 mmol) in toluene (45 ml), 4-chlorobenzylamine (2.56 mL, 21.1 mmol)was added. The resulting mixture was refluxed overnight with azeotropicremoval of water via a Dean-Stark trap. The reaction mixture wasconcentrated under reduced pressure to give 127 (5.90 g, 99%) as a redoil. This material was used without purification.

Step Two: To a solution of 127 (11.0 g, 39.3 mmol) in anhydrous THF (75mL) cooled to 0° C. under a dry, nitrogen atmosphere, NaH (60%dispersion in mineral oil, 1.73 g, 43.2 mmol) was added. The reactionwas stirred for 10 minutes at 0° C., then acetyl chloride (3.9 mL, 55mmol) was added. The reaction mixture was allowed to gradually warm toroom temperature, then was stirred overnight. The resulting mixture wasconcentrated under reduced pressure and a mixture of ice water (200 mL)and HCl (1 N, 200 mL) was added to the residue. This mixture wasextracted with ethyl acetate (300 mL) and the ethyl acetate layer wasdried over MgSO₄ and filtered. The filtrate was concentrated underreduced pressure to give 128 (13.4 g) as a brown oil. This materialcontained mineral oil but was used without purification.

Step Three: To a solution of crude 128 (13.4 g, 39.3 mmol theoretical)in anhydrous THF (50 ml) cooled to 0° C. under a dry, nitrogenatmosphere, lithium bis(trimethylsilyl)amide (1.0 M in THF, 125 mL, 125mmol) was added slowly via syringe. The reaction mixture was allowed towarm to room temperature, then was stirred overnight. The mixture wasconcentrated under reduced pressure and the residue was triturated withethyl acetate/hexane and filtered. The solid was washed with HCl (1 N,250 ml) and water (500 ml) to give 129 (5.48 g, 48% for two steps) as abrown solid.

(3S)-3-[({[1-(2-Chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was synthesized from 129 according to procedures described inExample 25. MS: Calculated (M+H)⁺=496.16 m/z. Found (M+H)⁺=495.99 m/z.

EXAMPLE 31 Synthesis of(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: To a solution of 46 (500 mg, 1.79 mmol) in anhydrous THF (10mL) cooled to 0° C. under a dry nitrogen atmosphere, NaH (60% dispersionin mineral oil, 210 mg, 5.37 mmol) was added and the resulting mixturewas stirred for 20 minutes. To this mixture, tert-butyl isocyanate (0.31mL, 2.68 mmol) was added and the reaction mixture was allowed to warm toroom temperature, then was stirred for 2 days. The reaction mixture wasquenched with water and extracted twice with ethyl acetate. The organiclayers were combined, dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure to give 130 (660 mg, 97%) as a brownsolid.

(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1-(2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was prepared from 130 according to procedures described in Example3. MS: Calculated (M−H)⁻=552.20 m/z. Found (M−H)⁻=551.89 m/z.

Synthetic procedures similar to those described above may be utilized toobtain the compounds of Tables 2, 3, 4 and 5.

EXAMPLE 32 Synthesis of(3S)-3-[({[5-chloro-1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid

Step One: To a solution of 31 (350 mg, 0.72 mmol) in CH₂Cl₂ at roomtemperature under a dry nitrogen atmosphere, sulfurylchloride (1.0 M inCH₂Cl₂, 0.65 mL, 0.65 mmol) was added by syringe. The resulting mixturewas stirred at room temperature for 1 hour, then was partitioned betweenCH₂Cl₂ and water. The organic layer was washed with brine and dried overMgSO₄ and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with 8:1,then 4:1 and finally 1:1 hexanes:ethyl acetate to give 131 (240 mg,64%).

(3S)-3-[({[5-Chloro-1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid was synthesized from 131 according to procedures described inExample 1. MS: Calculated (M−H)⁻=488.08; Found (M−H)⁻=487.97.

EXAMPLE 33 Synthesis of(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-ddihydropyridin-3-yl]amino}carbonyl)amino]-3-(2′,6′-dimethoxy-1,1′-biphenyl-4-yl)propanoicacid

Step One: To a solution of (R)-(+)-N-benzyl-α-methylbenzyl amine (5.07g, 24 mmol) in THF (85 mL) under nitrogen in a flame-dried flask, cooledto −78° C., sec-butyllithium (1.3 M solution in cyclohexane, 18.0 mL,23.4 mmol) was added dropwise over a 30 minute period. The mixture wasstirred an additional 30 minutes at −78° C., then a solution of t-butyl4-bromocinnamate (5.1 g, 20 mmol) in THF (20 mL) was added dropwise andthe mixture was allowed to come to room temperature overnight. Thereaction was quenched by addition of saturated ammonium chloride (˜50mL) and the organic layer was washed with saturated sodium chloride,dried over MgSO₄ then filtered. The filtrate was concentrated underreduced pressure and the residue was purified by silica gelchromatography eluting with hexanes and increasing to 3:1 hexanes:ethylacetate to give 132 (4.33 g, 47%) as a pale yellow oil.

Step Two: To a solution of 132 (7.4 g, 15 mmol) and 2,6-dimethoxyphenylboronic acid (4.9 g, 27 mmol) in DME (100 mL) at room temperature undera dry, nitrogen atmosphere, finely-powdered potassium phosphate (8.0 g,37.5 mM) and dichlorobis(triphenylphosphine)palladium (0) (0.5 g, 0.75mmol) were added. The mixture was deoxygenated (toggle between vacuumand nitrogen gas 5 times) and then heated to reflux for 8 hours. Themixture was then cooled and filtered through Celite® 521, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with hexanes increasingto 3:1 hexanes:ethyl acetate to give 133 (7.8 g, 95% yield).

Step Three: To a solution of 133 (3.39 g, 6.1 mmol) in ethanol (80 mL)in a 250 mL flask, acetic acid (0.5 mL) and palladium on carbon (10% Pddry weight basis, water content ˜50%, Degussa type E101 NE/W, 2.5 g, 1.2mmol Pd) were added sequentially. The mixture was stirred under ahydrogen atmosphere from a balloon for 36 hours. The reaction mixturewas filtered through Celite® 521 and the filtrate was concentrated underreduced pressure. The residue was recrystallized from ethyl acetate togive 134.HOAc (1.0 g, 71%) as a white solid.

(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2′,6′-dimethoxy-1,1′-biphenyl-4-yl)propanoicacid was synthesized from 134.HOAc by procedures described in Example25. MS: Measured (M+H)⁺=592.04; Calculated (M+H)⁺=592.19.

EXAMPLE 34 Synthesis of(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid

Step One: To a solution of sodium 1-butoxide (65 g, 0.642 mol) in THF (1L), at room temperature under a dry nitrogen atmosphere, ethanol (250mL, 5.35 mol) was added over a 10 minute period. To the resultingsolution, 2-chloro-6-fluorobenzonitrile (100 g, 0.642 mol) was added inportions. The reaction mixture was stirred at room temperature for 30minutes and then reduced to a volume of approximately 250 mL underreduced pressure. The resulting mixture was poured into chloroform andwater and the layers separated. The organic layer was washed with water(twice) and brine, dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure to afford a light yellow solid. Thismaterial was recrystallized from hexanes to provide the2-chloro-6-ethoxybenzonitrile, 135, (101 g, 87% yield) as a whitecrystalline solid.

Step Two: To a solution of 2-chloro-6-ethoxybenzonitrile, 135, (93.2 g,0.513 mol) in THF (350 mL) at room temperature under a dry nitrogenatmosphere was added borane in THF (1.0 M, 620 mL, 0.62 mol). Theresulting mixture was heated to reflux for 3 hours and then cooled toroom temperature. Water (250 mL) was added very slowly to the solutionallowing for the evolution of hydrogen. Concentrated HCl (50 mL) wasthen added over several minutes and the solution was heated to 50° C.for 2 hours. The mixture was cooled and partitioned between chloroformand water. The aqueous layer was washed 6 times with chloroform. Thecombined organic fractions were washed with HCl (1 M) and this organiclayer was discarded. Chloroform was added to the combined aqueous layersand solid KOH was added until the aqueous phase was basic (pH>9). Theaqueous layer washed with chloroform an additional five times. Theorganic fractions were combined and washed with water, brine, and driedover MgSO₄ and silica gel (2 g). This mixture was filtered and thefiltrate was concentrated under reduced pressure to give2-chloro-6-ethoxybenzylamine, 136, (60.1 g, 64% yield) as a light yellowoil.

Step Three: To a solution of 2-chloro-6-ethoxybenzylamine, 136, (7.30 g,39.3 mmol) in glacial acetic acid (50 mL) and acetic anhydride (50 mL)at room temperature, sodium nitrite (6.00 g, 85.7 mmol) was added insmall portions. The resulting mixture was stirred at room temperatureovernight then was poured into ice water and extracted with ethylacetate. The organic layer was washed with aqueous NaOH (1N, 2×100 mL)and brine (twice). The organic layer was dried over Na₂SO₄ and filteredand the filtrate was concentrated under reduced pressure to give 137(9.00 g, 100%) as a light yellow solid.

Step Four: To a solution of 137 (9.00 g, 39.3 mmol) andtetrabutylammonium bromide (1.0 g, 3.1 mmol) in THF (50 ml) at roomtemperature, aqueous NaOH (2N, 50 mL, 100 mmol) was slowly added and themixture was heated to 45° C. overnight. The reaction mixture was cooledto room temperature, then was diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and filtered and the filtrate was concentrated under reducedpressure to give 138 (7.08 g, 96% yield).

Step Five: To a solution of 138 (7.08 g, 37.9 mmol) in CH₂Cl₂ (55 mL) atroom temperature under a dry nitrogen atmosphere, a solution of SOCl₂(9.0 mL, 120 mmol) in CH₂Cl₂ (30 mL) was added dropwise. The resultingmixture was stirred at room temperature overnight, then was poured intoice water. The aqueous layer was extracted with CH₂Cl₂ and the combinedorganic layers were washed with aqueous NaOH (1N, twice), water (3times) and brine (twice). The organic layer was dried over Na₂SO₄ andfiltered and the filtrate was concentrated under reduced pressure togive 2-chloro-6-ethoxybenzylchloride, 139, (6.69 g, 86% yield) as aviscous, brown oil.

Step Six: A solution of 2-chloro-6-ethoxybenzychloride, 139, (6.90 g,33.7 mmol) and hydrazine (21.60 g, 673 mmol) in MeOH (22 mL) was stirredat room temperature for 3 hours. The mixture was then partitionedbetween CH₂Cl₂ and water. The organic layer was dried over MgSO₄ andfiltered and the filtrate was concentrated under reduced pressure togive 140 (6.18 g, 92%).

Step Seven: To a suspension of ethyl pyruvate (3.85 mL, 33.7 mmol) andMgSO₄ in CHCl₃ (65 mL), a solution of 140 (6.14 g, 30.6 mmol) in CHCl₃(30 mL) was slowly added. The resulting mixture was stirred at roomtemperature overnight. The resulting mixture was filtered and thefiltrate was concentrated under reduced pressure to give 141 (8.43 g,92%). This material was used in the next step without purification.

Step Eight: To a solution of 141 (8.43 g, 28.2 mmol) in dry THF (110 mL)cooled to 0° C. under a dry nitrogen atmosphere, sodium hydride (60%dispersion in mineral oil, 1.88 g, 47.1 mmol) was added in one portion.The resulting mixture was stirred at 0° C. for 30 minutes, then methylmalonylchloride (6.63 g, 47.10 mmol) was slowly added. The mixture wasallowed to warm to room temperature, stirred overnight, carefullyquenched with water then extracted with ethyl acetate (twice). Theorganic layers were combined, washed with brine, dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure to give142 (14.29 g). This material was used in the next step without furtherpurification.

Step Nine: To a solution of crude 142 (14.29 g) in dry DMF (60 mL)cooled to 0° C. under a dry nitrogen atmosphere, sodium hydride (60%dispersion in mineral oil, 2.90 g, 72.2 mmol) was added in one portion.This solution was heated to 60° C. overnight, cooled down in an icebath, then shaken with hexane. The layers were separated and the DMFlayer was poured into ice water. The mixture was acidified (pH 1) byadding HCl (2N). The precipitate was collected by filtration thedissolved in ethyl acetate. The organic solution was dried over MgSO₄and filtered and the filtrate was concentrated to give 143 (8.42 g, 85%yield for two steps).

Step Ten: A solution of 143 (8.42 g, 23.9 mmol) in dioxane (100 mL) andaqueous HCl (60 mL, 5.2 N) was refluxed overnight. The mixture wascooled to room temperature, diluted with water and extracted with ethylacetate. The organic layer was washed with brine, dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by silica gel chromatography eluting with 1:1 ethylacetate:hexanes, then ethyl acetate and finally 9:1 ethylacetate:methanol to give 144 (2.0 g, 28%).

Synthesis of(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6-methyl-3-oxo-2,3-dihydropyridazin-4-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid was prepared from 144 by procedures provided in Example 25. MS:Measured (M+H)⁺=545.05; Calculated (M+H)⁺=545.18.

EXAMPLE 35 Synthesis of (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)propanoicacid

Step One: An ice-cold mixture of sodium hydride (8.00 g, 60% dispersionin mineral oil, 200 mmol) and 145 (8.94 g, 66.6 mmol) in DMF (250 mL)under a dry nitrogen atmosphere was allowed to gradually warm to roomtemperature. To the resulting mixture, iodoethane (16 ml, 200 mmol) wasadded and the mixture was stirred at room temperature overnight. Thereaction mixture was poured into ice and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure and theresidue was taken up in hexanes and filtered. The resulting brown solidwas dried under reduced pressure to give 146 (9.00 g, 71% yield). Thismaterial was used without purification.

Step Two: A mixture of DMF (3.6 g, 49 mmol) and POCl₃ (9.6 mL, 100 mmol)was stirred at room temperature under a dry nitrogen atmosphere for 1hour. The flask containing this mixture was then placed in a 45° C. oilbath and 146 (7.6 g, 40 mmol) was added in small portions. The oil bathtemperature was raised to 70° C. and the mixture was stirred overnight,then cooled to room temperature. The mixture was diluted with water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure to give a 7:3 mixture of 147:146 (6.69 g). Thismaterial was used without purification.

Step Three: To a solution of the 147:146 mixture obtained above (2.2 g)in ethanol (2.2 mL), malonic acid (1.16 g, 11.2 mmol), pyridine (0.44mL) and piperidine (0.99 mL) were added sequentially. The resultingmixture was heated to reflux for 6 hours, then cooled to roomtemperature. The mixture was diluted with aqueous NaOH (1N) andextracted with ethyl acetate (4 times). The aqueous phase was acidifiedto pH 3 with HCl (1N) and the resulting suspension was filtered, washingthe solid with water. The white solid was collected and dried underreduced pressure to give 148 (1.69 g, 49% for two steps).

(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)propanoicacid was prepared from 148 by procedures described in Examples 33 and25. MS: Measured (M+H)⁺=594.05; Calculated (M+H)⁺=594.21.

EXAMPLE 36 Synthesis of give(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid, 153

Step One: To a solution of 114 (20.3 g, 129 mmol) in anhydrous methanol(430 mL) at room temperature under a dry nitrogen atmosphere,2-chloro-6-ethoxybenzylamine, 136, (31.1 g, 168 mmol) was added. Thesolution was heated at 45° C. for 1 hour then refluxed overnight. Thereaction mixture was cooled to room temperature and concentrated todryness. The residue was brought up in dichloromethane and filtered. Thesolid was collected and dried under vacuum to give 149 (14.7 g, 39%).

Step Two: To a suspension of 149 (11.02 g, 37.8 mmol) in glacial aceticacid (126 mL) at room temperature, NaNO₂ (522 mg, 7.6 mmol), water (10.5mL) and HNO3 (70%, 9.6 mL, 151.2 mmol) were added sequentially. Theresulting bright yellow solution was stirred at room temperatureovernight, then was diluted with CH₂Cl₂ and water. The aqueous phase wasextracted with CH₂Cl₂, the organic layers were combined and washed withwater (3 times) and brine. The organic layer was dried over MgSO₄ andfiltered and the filtrate was concentrated under reduced pressure. Theresidue was recrystallized from CH₂Cl₂/ethyl acetate to give 150 (10.9g, 85%) as a bright yellow solid.

Step Three: To a solution of 150 (10.9 g, 32.2 mmol) in DMF (107 mL) atroom temperature under a dry nitrogen atmosphere, Zn powder (9.48 g, 145mmol) and triethylamine hydrochloride (24.4 g, 177 mmol) were added. Theresulting mixture was heated to 55° C. for 1 h, then was cooled to roomtemperature. To the resulting mixture, CDI (10.4 g, 64.4 mmol) was addedas a solid. Upon addition, gas evolution occurred. The mixture was thenheated to 80° C. for 2 hours, cooled to room temperature and poured intoHCl (2 N, 1 L). The resulting suspension was stirred for 20 minutes andthen was diluted with water (1 L) and filtered. The solid wasresuspended in water (1 L) and then filtered. The solid was dried undervacuum to give 151 (10.78 g, 100% yield) as a white powder.

Step Four: A mixture of 151 (10.68 g, 31.9 mmol) and 8 (8.27 g, 39.9mmol) in DMF (64 mL) under a dry nitrogen atmosphere was heated to 55°C. overnight, cooled to room temperature and then diluted with ethylacetate. The resulting mixture was washed with HCl (2N), water (4 times)and brine and the organic layer was dried over MgSO₄ and filtered. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by silica gel chromatography, eluting with 7:3hexanes:ethyl acetate to give 152 (14.2 g, 82%) as a pale yellow foam.

Step Five: To a solution of 152 (11.60 g, 21.4 mmol) in THF (138 mL) atroom temperature, aqueous sodium hydroxide (2 N, 46 mL) and methanol (92mL) were added. The mixture was stirred for 20 minutes, then was dilutedwith water and extracted with ethyl ether. The aqueous phase wasacidified with HCl (2 N) and extracted with ethyl acetate. The ethylacetate layer was washed with water and brine, dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure to give(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid, 153, (10.82, 98% yield) as a light tan foam. MS: Calculated(M−H)⁻=512.16; Measured (M−H)⁻=512.03.

EXAMPLE 37 Synthesis of(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid, 156

Step One: A mixture of 151 (8.40 g, 28.8 mmol) and 154 (8.2 g, 35 mmol)in DMF (100 mL) under a dry nitrogen atmosphere was heated to 55° C.overnight, cooled to room temperature and then diluted with ethylacetate. The resulting mixture was washed with HCl (2N), water (4 times)and brine and the organic layer was dried over MgSO₄ and filtered. Thefiltrate was concentrated under reduced pressure and the resultingresidue was purified by silica gel chromatography, eluting with 8:2increasing to 1:1 hexanes:ethyl acetate to give 155 (11.1 g, 67% yield).

Step Two: To a solution of 155 (9.12 g, 15.9 mmol) in THF (100 mL) atroom temperature, aqueous sodium hydroxide (1 N, 88 mL) and methanol (63mL) were added. The mixture was stirred for 20 minutes, then was dilutedwith water and extracted with ethyl ether. This ether layer wasdiscarded. The aqueous phase was acidified with HCl (2 N) and extractedwith ethyl ether (4 times). The organic layers were washed with waterand brine, dried over MgSO₄ and filtered. The filtrate was concentratedunder reduced pressure to give(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid, 156, (8.13 g, 93%) as a white foam. MS: Calculated (M+H)⁺=544.19;Measured (M+H)⁺=544.04.

EXAMPLE 38 Synthesis of(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoicacid, 159

Step One: A mixture of 151 (110 mg, 0.29 mmol), 157 (130 mg, 0.34 mmol)and NMM (0.50 mL, 4.5 mmol) in DMF (1.0 mL) under a dry nitrogenatmosphere was heated to 55° C. overnight, cooled to room temperatureand then diluted with ethyl acetate. The resulting mixture was washedwith HCl (2N), water (4 times) and brine and the organic layer was driedover MgSO₄ and filtered. The filtrate was concentrated under reducedpressure and the resulting residue was purified by silica gelchromatography, eluting with 1:1 hexanes:ethyl acetate to give 158 (130mg, 73% yield).

Step Two: To a solution of 158 (130 mg, 0.21 mmol) in THF (3 mL) at roomtemperature, aqueous sodium hydroxide (2 N, 1 mL) and methanol (2 mL)were added. The mixture was stirred for 20 minutes, then was dilutedwith water and extracted with ethyl ether. The aqueous phase wasacidified with HCl (2 N) and extracted with ethyl acetate. The ethylacetate layer was washed with water and brine, dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure to give(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoicacid, 159, (90 mg, 74% yield). MS: Measured (M+H)⁺=580.07; Calculated(M+H)⁺=580.19.

EXAMPLE 39 Synthesis of(3S)-3-[({[1-(2-chlorobenzyl)4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid, 164

Step One: To a suspension of 129 (5.30 g, 19.2 mmol) in glacial aceticacid (64 mL) at room temperature, NaNO₂ (266 mg, 3.9 mmol), water (5.3mL) and HNO₃ (70%, 4.9 mL, 77 mmol) were added sequentially. Theresulting bright yellow solution was stirred at room temperatureovernight, then was poured into water and filtered, washing with water.The yellow solid was dried under reduced pressure to give 160 (5.35 g,87%).

Step Two: To a solution of 160 (5.35 g, 16.7 mmol) in DMF (56 mL) atroom temperature under a dry nitrogen atmosphere, Zn powder (4.88 g,74.7 mmol) and triethylamine hydrochloride (12.6 g, 91.5 mmol) wereadded. The resulting mixture was heated to 55° C. for 1 h, then wascooled to room temperature. To the resulting mixture, CDI (5.41 g, 33.4mmol) was added as a solid. Upon addition, gas evolution occurred. Themixture was then heated to 80° C. for 2 hours, cooled to roomtemperature and poured into HCl (2 N, 500 mL). The resulting suspensionwas stirred for 20 minutes and then was diluted with water (500 mL) andfiltered. The solid was resuspended in water (500 mL) and then filtered.The solid was dried under vacuum to give 161 (5.0 g, 95% yield) as awhite powder.

Step Three: A mixture of 161 (6.14 g, 19.4 mmol) and 162 (5.12 g, 20.3mmol) in DMF (90 mL) under a dry nitrogen atmosphere was heated to 80°C. overnight, cooled to room temperature and then diluted with ethylacetate. The resulting mixture was washed with HCl (2 N), water (4times) and brine and the organic layer was dried over MgSO₄ andfiltered. The filtrate was concentrated under reduced pressure and theresulting residue was purified by silica gel chromatography, elutingwith 7:3 hexanes:ethyl acetate to give 163 (8.90 g, 81%) as a paleyellow foam.

Step Four: To a solution of 163 (8.69 g, 15.3 mmol) in THF (35 mL) atroom temperature, aqueous sodium hydroxide (2 N, 30 mL) and methanol (30mL) were added. The mixture was stirred overnight, then was diluted withwater and extracted with ethyl ether. The aqueous phase was acidifiedwith HCl (2 N) and extracted with ethyl acetate. The ethyl acetate layerwas washed with water and brine, dried over MgSO₄ and filtered. Thefiltrate was concentrated under reduced pressure to give(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid, 164, (7.50 g, 91% yield). MS: Measured (M+H)⁺=540.09; Calculated(M+H)⁺=540.19.

EXAMPLE 40 Synthesis of(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propanoicacid

Step One: To a mixture of 162 (200 mg, 0.80 mmol) in glacial acetic acid(1.65 mL) cooled to 0° C. under a dry nitrogen atmosphere, a mixture ofSO₂Cl₂ (1.2 mL, 15 mmol) in glacial acetic acid (1.0 mL) was addeddropwise by syringe. The resulting mixture was stirred at 0° C. for 30minutes then was warmed to room temperature. After stirring for anadditional 4 hours, the mixture was recooled to 0° C. and quenched bycareful addition of saturated aqueous NaHCO₃. The mixture was extractedwith ethyl acetate and the organic layer was washed with saturatedaqueous NaHCO₃, dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography, eluting with 2:1 hexanes:ethyl acetate togive 165 (148 mg, 65%).

(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propanoicacid was prepared from 165 according to procedures described in Examples25 and 30. MS: Calculated (M−H)⁻=586.15; Found (M−H)⁻=585.92.

EXAMPLE 41 Synthesis of(3S)-3-({[(1-{[2-chloro-6-tetrahydro-1(2H)-pyridinylphenyl]methyl}-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoicacid

Step One: To a suspension of 166 (0.35 g, 1.06 mmol, prepared accordingto procedures described in Examples 34 and 25) in methanol (7 mL) andwater (3.5 mL) cooled to 0° C., glacial acetic acid (189 μL, 3.2 mmol)and sodium nitrite (178 mg, 2.65 mmol) were added sequentially. Themixture was allowed to slowly warm to room temperature overnight andthen was diluted with chloroform and water. The pH of the aqueous phasewas checked to ensure a pH of 4-5. The organic layer was washed withbrine, dried over MgSO₄ and filtered and the filtrate was concentratedunder reduced pressure to give 167 (0.35 g, 92%) as a yellow solid.

(3S)-3-({[(1-{[2-chloro-6-tetrahydro-1(2H)-pyridinylphenyl]methyl}-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoicacid was synthesized from 167 according to the procedures described inExample 25. MS:

Calculated (M−H)⁻=551.21; Found (M−H)⁻=551.06.

EXAMPLE 42 Synthesis of (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoicacid

Step One: To a solution of 3-bromobenzaldehyde, 168, (3.00 g, 16.2 mmol)in DMF (69 mL) under a dry nitrogen atmosphere, palladium acetate (73mg, 0.32 mmol), tri-o-tolylphosphine (197 mg, 0.65 mmol), ethyl acrylate(2.20 mL, 20.3 mmol) and triethylamine (4.50 mL, 32.4 mmol) were added.The system was deoxygenated (toggle between vacuum and nitrogen fivetimes), the mixture was heated to 125° C. for 19 hours and then cooledto room temperature. The reaction was poured into water and extractedwith ether. The organic layer was washed with HCl (4N) and brine, driedover MgSO₄ and filtered. The filtrate was concentrated under reducedpressure to give 169 (2.74 g, 83%), which was used without furtherpurification.

Step Two: To a flask containing 169 (1.00 g, 4.9 mmol) under a drynitrogen atmosphere, (dimethylamino)sulfur trifluoride (0.96 mL, 9.8mmol) was added by syringe.

The mixture was heated to 90° C. behind a blast shield for 25 minutesthen was cooled to room temperature. The resulting mixture was dilutedwith CH₂Cl₂ and washed with saturated aqueous NaHCO₃ and H₂O. Theorganic layer was dried over MgSO₄ and filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with 1:5 ethyl actetate:hexanes to give 170(0.62 g, 56%).

Step Three: To a solution of (R)-(+)-N-benzyl-α-methylbenzylamine (0.70g, 3.3 mmol) in THF (6.7 mL) cooled to −78° C. under a dry nitrogenatmosphere, sec-BuLi (4.22 mL, 1.3M in cyclohexane, 5.5 mmol) was addeddropwise. The resulting mixture was stirred at −78° C. for 30 minutesand then a solution of 170 (0.62 g, 2.74 mmol) in THF (3.4 mL) was addeddropwise by syringe. The mixture was stirred at −78° C. for 5 hours andthen quenched with glacial AcOH (2 mL) in THF (5 mL). The reactionmixture was warmed to room temperature, poured into a 1:1 mixture ofsaturated aqueous NaHCO₃:EtOAc. The organic layer was washed with H₂O (2times) and brine, dried over MgSO₄ and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography, eluting with 1:5 ethyl actetate:hexanes togive 171 (1.2 g, 100%). This material still contained minor impuritiesbut was used without further purification.

Step Four: To a solution of 171 (0.50 g, 1.14 mmol) in EtOH (10 mL) atroom temperature under a dry nitrogen atmosphere, Pd/C (10% Pd dryweight basis, 50% water by weight, Degussa type E101 NE/W, 0.25 g) andglacial AcOH (0.5 mL) were added. The atmosphere was replaced byhydrogen (toggle between vacuum and hydrogen from a balloon five times)and the mixture was heated to 35° C. for 6 hours. The reaction wascooled to room temperature, filtered through a plug of Celite® 521 andthe filtrate was concentrated under reduced pressure. The residue wasdiluted with CHCl₃ and washed with saturated aqueous NaHCO₃. The aqueouslayer was extracted with CHCl₃ (2 times) and the combined organic layerswere dried over MgSO₄ and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by silica gelchromatography, eluting with 1:10 MeOH:CHCl₃ to give 172 (180 mg, 67%).

(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoicacid was synthesized from 172 according to procedures described inExample 25. MS: Calculated (M−H)⁻=504.11; Found (M−H)⁻=503.96.

EXAMPLE 43

The procedures described in Examples 3, 4, 8, 25, 26, 27, 29, 30, 34,36, 39 and 41 were utilized to synthesize several compounds of generalFormula VII and general Formula VIII, by varying starting materials. InTable 1 shown below, characterization data is provided for compoundssynthesized.

TABLE 1 Compound ¹H NMR (400 MHz) 5-(2-chlorobenzyl)-3,5- (CD₃SO₂CD₃) δ5.27(s, 2H), 6.67(d, J=7.4 Hz, dihydro[1,3]oxazolo[4,5- 1H), 6.88(dd,J=7.3, 1.4 Hz, 1H), c]pyridine-2,4-dione 7.27-7.37(m, 2H), 7.51(dd,J=7.9, 1.5 Hz, 1H), 7.65(d, J=7.4 Hz, 1H), 12.01(br. s, 1H).5-(2-chlorobenzyl)-6-methyl- (CD₃SO₂CD₃) δ 2.27(s, 3H), 5.36(s, 2H),3,5-dihydro[1,3]oxazolo[4,5- 6.60(d, J=7.3 Hz, 1H), 6.63(s, 1H),c]pyridine-2,4-dione 7.27-7.37(m, 2H), 7.51(d, J=7.7 Hz, 1H), 11.9(br.s, 1H). 5-(2-fluorobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.26(s, 2H), 6.65(d, J=7.3Hz, dihydro[1,3]oxazolo[4,5- 1H), 6.88, 7.12-7.26(m, 3H), 7.37(m,c]pyridine-2,4-dione 1H), 7.69(d, J=7.3 Hz, 1H), 11.93(br. s, 1H).5-(2-chloro-6-fluorobenzyl)- (CD₃SO₂CD₃) δ 5.30(s, 2H), 6.56(d, J=7.3Hz, 3,5-dihydro[1,3]oxazolo[4,5- 1H), 7.25(ddd, J=9.4, 8.9, 1.1 Hz,c]pyridine-2,4-dione 1H), 7.37(d, J=8.0 Hz, 1H), 7.43(m, 2H), 11.93(br.s, 1H). 5-benzyl-6-methyl-3,5- (CD₃SO₂CD₃) δ 2.30(s, 3H), 5.37(s, 2H),dihydro[1,3]oxazolo[4,5- 6.55(s, 1H), 7.10(d, J=7.0 Hz, 2H),c]pyridine-2,4-dione 7.24-7.36(m, 3H), 11.88(br. s, 1H). 5-benzyl-3,5-(CD₃SO₂CD₃) δ 5.20(s, 2H), 6.60(d, J=7.3 Hz, dihydro[1,3]oxazolo[4,5-1H), 7.28-7.36(m, 5H), 7.72(d, J=7.3 Hz, c]pyridine-2,4-dione 1H),11.97(br. s, 1H). 5-(2,5-dimethylbenzyl)-3,5- (CDCl₃) δ 2.27(s, 3H),2.32(s, 3H), 5.27(s, dihydro[1,3]oxazolo[4,5- 2H), 6.42(d, J=7.3 Hz, 1H)6.90(s, 1H), c]pyridine-2,4-dione 7.09(m, 3H), 10.68(br s, 1H).5-(2-methylbenzyl)-3,5- (CDCl₃) δ 2.30(s, 3H), 5.28(s, 2H), 6.39(d,J=7.3 Hz, dihydro[1,3]oxazolo[4,5- 1H), 7.06(d, J=7.3 Hz, 1H),c]pyridine-2,4-dione 7.09(d, J=7.7 Hz, 1H), 7.18-7.28(m, 3H) 10.91(br s,1H). 5-(2,4-dichlorobenzyl)-3,5- (CDCl₃) δ 5.33(s, 2H), 6.47(d, J=7.3Hz, dihydro[1,3]oxazolo[4,5- 1H), 7.29(m, 1H), 7.38(d, J=7.3 Hz, 1H),c]pyridine-2,4-dione 7.42-7.48(m, 2H) 10.77(br s, 1H).5-(2-methoxybenzyl)-3,5- (CDCl₃) δ 3.87(s, 1H), 5.24(s, 2H), 6.36(d,J=7.5 Hz, dihydro[1,3]oxazolo[4,5- 1H), 6.88(d, J=8.1 Hz, 1H),c]pyridine-2,4-dione 6.97(m, 1H), 7.30(m, 1H), 7.45(d, J=7.5 Hz, 1H),7.55(m, 1H), 10.75(br. s, 1H). 5-(2,5-difluorobenzyl)-3,5- (CDCl₃) δ5.26(s, 2H), 6.46(d, J=7.4 Hz, dihydro[1,3]oxazolo[4,5- 1H),6.96-7.05(m, 2H), 7.30-7.37(m, 1H), c]pyridine-2,4-dione 7.39(m, 1H),10.68(br. s, 1H). 5-[2-chloro-5- (CD₃SO₂CD₃) δ 2.41(s, 3H), _5.24(s,2H), (methylthio)benzyl]-3,5- 6.65(d, J=7.2 Hz, 1H), 6.83(d, J=2.6 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.25(dd, J=8.0, 2.6 Hz, 2H), 7.45(d, J=8.0Hz, c]pyridine-2,4-dione 1H), 7.62(d, J=7.2 Hz, 1H), 12.01(br. s, 1H).5-(4-fluorobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.18(s, 2H), 6.61(d, J=7.4 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.14-7.2(m, 2H), 7.35-7.39(m, 2H),c]pyridine-2,4-dione 7.74(d, J=7.3 Hz, 1H), 11.96(br. s, 1H).5-(2-chloro-5-methoxybenzyl)- (CD₃SO₂CD₃) δ 3.69(s, 3H), 5.22(s, 2H),3,5-dihydro[1,3]oxazolo[4,5- 6.42(d, J=2.9 Hz, 1H), 6.65(d, J=7.3 Hz,c]pyridine-2,4-dione 1H), 6.94(dd, J=8.8, 2.9 Hz, 1H), 7.43(d, J=8.8 Hz,1H), 7.62(d, J=7.3 Hz, 1H), 12.05(br. s, 1H). 5-[3,5- (CD₃SO₂CD₃) δ5.36(s, 2H), 6.69(d, J=7.5 Hz, bis(trifluoromethyl)benzyl]- 1H), 7.91(d,J=7.5 Hz, 1H), 8.08(s, 3,5-dihydro[1,3]oxazolo[4,5- 3H), 12.04(br. S,1H). c]pyridine-2,4-dione 5-(4-tert-butylbenzyl)-3,5- (CD₃SO₂CD₃) δ1.24(s, 9H), 5.15(s, 2H), dihydro[1,3]oxazolo[4,5- 6.61(d, J=7.3 Hz,1H), 7.23(d, J=8.4 Hz, c]pyridine-2,4-dione 2H), 7.35(d, J=8.4 Hz, 2H),7.74(d, J=7.3 Hz, 1H), 12.02(br. s, 1H). 5-(3-chlorobenzyl)-3,5-(CD₃SO₂CD₃) δ 5.20(s, 2H), 6.63(d, J=7.4 Hz, dihydro[1,3]oxazolo[4,5-1H), 7.25(m, 1H), 7.35-7.39(m, 3H), c]pyridine-2,4-dione 7.76(d, J=7.4Hz, 1H), 11.97(br. s, 1H). 5-(4-chlorobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.19(s,2H), 6.62(d, J=7.3 Hz, dihydro[1,3]oxazolo[4,5- 1H), 7.29-7.33(m, 2H),7.37-7.42(m, c]pyridine-2,4-dione 2H), 7.73(d, J=7.3 Hz, 1H), 11.97(br.s, 1H). 5-[3-(trifluoromethyl)benzyl]- n.d. 3,5-dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione 5-(2-bromobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.23(s, 2H),6.68(d, J=7.4 Hz, dihydro[1,3]oxazolo[4,5- 1H), 6.79(m, 1H), 7.26(m,1H), 7.34(m, c]pyridine-2,4-dione 1H), 7.64(d, J=7.4 Hz, 1H), 7.68(m,1H), 12.02(br. s, 1H). 5-(3,4-dichlorobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.19(s,2H), 6.64(d, J=7.3 Hz, dihydro[1,3]oxazolo[4,5- 1H), 7.29(m, 1H),7.61(m, 2H), 7.77(d, c]pyridine-2,4-dione J=7.3 Hz, 1H), 11.98(br. s,1H). 5-(4-methylbenzyl)-3,5- (CD₃SO₂CD₃) δ 2.27(s, 3H), 5.14(s, 2H),dihydro[1,3]oxazolo[4,5- 6.59(d, J=7.5 Hz, 1H), 7.14(d, J=8.2 Hz,c]pyridine-2,4-dione 2H), 7.20(d, J=8.2 Hz, 2H), 7.69(d, J=7.5 Hz, 1H),11.95(br. s, 1H). 5-(2-chloro-6-methoxybenzyl)- (CD₃SO₂CD₃) δ 3.80(s,3H), 5.23(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5- 6.48(d, J=7.4 Hz, 1H),7.05-7.15(m, 3H), c]pyridine-2,4-dione 7.42(m, 1H), 11.95(br. s, 1H).5-[4-(trifluoromethyl)benzyl]- (CD₃SO₂CD₃) δ 5.30(s, 2H), 6.65(d, J=7.3Hz, 3,5-dihydro[1,3]oxazolo[4,5- 1H), 7.48(d, J=8.0 Hz, 2H), 7.71(d,J=8.0 Hz, c]pyridine-2,4-dione 2H), 7.76(d, J=7.3 Hz, 1H), 11.96(br. s,1H). 5-(3-methylbenzyl)-3,5- (CD₃SO₂CD₃) δ 2.27(s, 3H), 5.15(s, 2H),dihydro[1,3]oxazolo[4,5- 6.62(d, J=7.3 Hz, 1H), 7.10(m, 4H),c]pyridine-2,4-dione 7.72(d, J=7.3 Hz, 1H), 12.53(br. s, 1H).5-(pyridin-2-ylmethyl)-3,5- (CD₃SO₂CD₃) δ 5.29(s, 2H), 6.62(d, J=7.3 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.22-7.33(m, 2H), 7.71(d, J=7.3 Hz,c]pyridine-2,4-dione 1H), 7.79(m, 1H), 8.50(m, 1H), 11.96(br. s, 1H).5-(2-chlorobenzyl)-7-methyl- (CD₃SO₂CD₃) δ 2.10(s, 3H), 5.23(s, 2H),3,5-dihydro[1,3]oxazolo[4,5- 6.86(dd, J=7.7, 1.5 Hz, 1H), 7.31(m, 2H),c]pyridine-2,4-dione 7.50(m, 2H), 12.01(br s, 1H).5-(2,4-difluorobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.21(s, 2H), 6.63(d, J=7.3 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.02-7.07(m, 1H), 7.20-7.29(m,c]pyridine-2,4-dione 2H), 7.65(d, J=7.3 Hz, 1H), 11.97(br. s, 1H).5-(2,6-difluorobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.25(s, 2H), 6.58(d, J=7.3 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.02-7.12(m, 2H) 7.38-7.55(m,c]pyridine-2,4-dione 1H), 7.63(d, J=7.3 Hz, 1H), 11.91(br. s, 1H). 5-[3-(CD₃SO₂CD₃) δ 5.24(s, 2H), 6.64(d, J=7.3 Hz,(trifluoromethoxy)benzyl]-3,5- 1H), 7.22-7.35(m, 3H), 7.46(t, J=7.7 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.78(d, J=7.3 Hz, 1H), 11.99(br. s,c]pyridine-2,4-dione 1H). 5-[4- (CD₃SO₂CD₃) δ 5.23(s, 2H), 6.63(d, J=7.3Hz, (trifluoromethoxy)benzyl]-3,5- 1H), 7.29-7.45(m, 4H), 7.76(d, J=7.3Hz, dihydro[1,3]oxazolo[4,5- 1H), 11.98(br. s, 1H). c]pyridine-2,4-dione5-[2-(trifluoromethyl)benzyl]- (CD₃SO₂CD₃) δ 5.40(s, 2H), 6.73(d, J=7.3Hz, 3,5-dihydro[1,3]oxazolo[4,5- 1H), 6.81(d, J=7.5 Hz, 1H), 7.51(t,J=7.5 Hz, c]pyridine-2,4-dione 1H), 7.61(t, J=7.5 Hz, 1H), 7.70(d, J=7.3Hz, 1H), 7.80(d, J=7.5 Hz, 1H), 12.04(br. s, 1H).5-(3-methoxybenzyl)-3,5- n.d. dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione 5-(2,3-dichlorobenzyl)-3,5- n.d.dihydro[1,3]oxazolo[4,5- c]pyridine-2,4-dione5-(3,5-dimethylbenzyl)-3,5- (CD₃SO₂CD₃) δ 2.23(s, 6H), 5.11(s, 2H),dihydro[1,3]oxazolo[4,5- 6.61(d, J=7.3 Hz, 1H), 6.91(m, 3H),c]pyridine-2,4-dione 7.69(d, J=7.3 Hz, 1H), 12.00(br. s, 1H).5-(2-chlorobenzyl)-7-pentyl- (CD₃SO₂CD₃) δ 0.86(t, J=6.2 Hz, 3H),3,5-dihydro[1,3]oxazolo[4,5- 1.27(m, 6H), 1.65(t, J=6.7 Hz, 2H), 5.24(s,2H), c]pyridine-2,4-dione 6.83(d, J=6.6 Hz, 1H), 7.24-7.34(m, 2H),7.48(s, 1H), 7.50(d, J=7.7 Hz, 1H), 12.00(br. s, 1H).5-(2,4-dichlorobenzyl)-7- (CD₃SO₂CD₃) δ 2.10(s, 3H), 5.19(s, 2H),methyl-3,5- 6.87(d, J=8.4 Hz, 1H), 7.38(dd, J=8.4, 2.2 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.50(s, 1H), 7.69(d, J=2.2 Hz,c]pyridine-2,4-dione 1H), 12.02(br. s, 1H).5-(2-chlorobenzyl)-7-ethyl-3,5- (CD₃SO₂CD₃) δ 1.17(t, J=7.5 Hz, 3H),dihydro[1,3]oxazolo[4,5- 2.50(m, 2H overlapping DMSO), 5.25(s, 2H),c]pyridine-2,4-dione 6.84(m, 1H), 7.30(m, 2H), 7.49(m, 2H), 12.02(br. s,1H). 7-butyl-5-(2-chlorobenzyl)- (CD₃SO₂CD₃) δ 0.87(t, J=7.3 Hz, 3H),3,5-dihydro[1,3]oxazolo[4,5- 1.28(m, 4H), 1.54(t, J=7.1 Hz, 2H), 5.24(s,2H), c]pyridine-2,4-dione 6.83(d, J=6.8 Hz, 1H), 7.24-7.34(m, 2H),7.48-7.56(m, 2H), 12.00(br. s, 1H). 5-[2-chloro-5- (CD₃SO₂CD₃) δ 5.33(s,2H), 6.68(d, J=7.3 Hz, (trifluoromethyl)benzyl]-3,5- 1H), 7.35(s, 1H),7.69-7.79(m, 3H), dihydro[1,3]oxazolo[4,5- 11.96(br. s, 1H).c]pyridine-2,4-dione 5-(2,6-dichlorobenzyl)-3,5- (CD₃SO₂CD₃) δ 5.38(s,2H), 6.53(d, J=7.4 Hz, dihydro[1,3]oxazolo[4,5- 1H), 7.07(d, J=7.7 Hz,1H), c]pyridine-2,4-dione 7.45-7.50(m, 1H), 7.52-7.59(m, 2H), 11.99(br.s, 1H). 5-(2-chloro-5-fluorobenzyl)- (CD₃SO₂CD₃) δ 5.27(s, 2H), 6.67(d,J=7.3 Hz, 3,5-dihydro[1,3]oxazolo[4,5- 1H), 6.72(dd, J=7.3, 3.2 Hz, 1H),c]pyridine-2,4-dione 7.21-7.23(m, 1H), 7.55-7.59(m, 1H), 7.65(d, J=7.3Hz, 1H), 12.00(br. s, 1H). 5-(2-chloro-6-methylbenzyl)-7- (CDCl₃) δ2.07(s, 3H), 2.29(s, 3H), 5.48(s, methyl-3,5- 2H), 6.63(s, 1H), 7.16(d,J=7.7 Hz, 1H), dihydro[1,3]oxazolo[4,5- 7.25(t, J=7.7 Hz, 1H), 7.34(d,J=7.7 Hz, c]pyridine-2,4-dione 1H), 11.33(br. S, 1H).5-(4-chlorobenzyl)-7-methyl- (CD₃SO₂CD₃) δ 2.08(s, 3H), 5.14(s, 2H),3,5-dihydro[1,3]oxazolo[4,5- 7.31(d, J=8.4 Hz, 2H), 7.41(d, J=8.4 Hz,c]pyridine-2,4-dione 2H), 7.58(s, 1H), 12.03(br. s, 1H).5-(2-chlorobenzyl)-5,6,7,8- (CD₃SO₂CD₃) δ 2.04(m, 2H), 2.80(m, 4H),tetrahydro-2H- 5.28(s, 2H), 6.68(d, J=7.3 Hz, 1H),cyclopenta[b][1,3]oxazolo[5,4- 7.18-7.34(m, 2H), 7.51(d, J=7.7 Hz, 1H),d]pyridine-2,4(3H)-dione 11.92(br. s, 1H). 7-methyl-5-[4- (CD₃SO₂CD₃) δ2.11(s, 3H), 2.58(s, 3H), (methylsulfonyl)benzyl]-3,5- 5.28(s, 2H),7.58(d, J=7.3 Hz, 2H), 7.64(s, dihydro[1,3]oxazolo[4,5- 1H), 7.91(d,J=7.3 Hz, 2H), 12.06(br. s, c]pyridine-2,4-dione 1H).5-(4-methoxybenzyl)-3,5- (CD₃SO₂CD₃) δ 3.73(s, 3H), 5.10(s, 2H),dihydro[1,3]oxazolo[4,5- 6.56(br. d, J=5.9 Hz, 1H), 6.89(d, J=8.8 Hz,c]pyridine-2,4-dione 2H), 7.27(d, J=8.8 Hz, 2H), 7.67(br. m, 1H),12.06(br. s, 1H). 5-(2-chlorobenzyl)-7-propyl- (CD₃SO₂CD₃) δ 0.88(t,J=7.4 Hz, 3H), 3,5-dihydro[1,3]oxazolo[4,5- 1.57(m, 2H), 2.46(m, 2H),5.24(s, 2H), 6.84(d, J=6.2 Hz, c]pyridine-2,4-dione 1H), 7.26-7.38(m,2H), 7.48(s, 1H), 7.50(d, J=7.7 Hz, 1H), 12.00(br. s, 1H).4-[(2,4-dioxo-2,3- (CD₃SO₂CD₃) δ 2.55(s, 6H), 5.31(s, 2H),dihydro[1,3]oxazolo[4,5- 6.67(d, J=7.3 Hz, 1H), 7.43-7.51(m, 2H),c]pyridin-5(4H)-yl)methyl]- 7.66-7.74(m, 2H), 7.77(d, J=7.3 Hz, 1H),N,N- 12.00(br. s, 1H). dimethylbenzenesulfonamide 5-(mesitylmethyl)-3,5-(CDCl₃) δ 2.19(s, 6H), 2.30(s, 3H), 5.25(s, dihydro[1,3]oxazolo[4,5-2H), 6.31(d, J=7.3 Hz, 1H), 6.73(d, J=7.3 Hz, c]pyridine-2,4-dione 1H),6.94(s, 2H), 11.01(br. s, 1H). 5-(2-chlorobenzyl)-3,5,6,7,8,9-(CD₃SO₂CD₃) δ 1.64(m, 4H), 2.50(m, 4H), hexahydro[1,3]oxazolo[4,5-5.34(s, 2H), 6.59(d, J=8.1 Hz, 1H), c]quinoline-2,4-dione 7.25-7.34(m,2H), 7.51(d, J=7.7 Hz, 1H), 11.92(br. s, 1H).5-(2-chlorobenzyl)-7-ethyl-6- (CD₃SO₂CD₃) δ 1.10(t, J=7.4 Hz, 3H),methyl-3,5- 2.22(s, 3H), 2.56(m, 2H), 5.40(s, 2H), 6.58(d, J=7.0 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.23-7.34(m, 2H), 7.52(d, J=8.1 Hz,c]pyridine-2,4-dione 1H), 11.92(br. s, 1H).5-[2-(methylthio)benzyl]-3,5- (CD₃SO₂CD₃) δ 2.52(s, 3H), 5.19(s, 2H),dihydro[1,3]oxazolo[4,5- 6.63(d, J=7.3 Hz, 1H), 6.76(d, J=7.7 Hz,c]pyridine-2,4-dione 1H), 7.09-7.17(m, 1H), 7.29-7.37(m, 2H), 7.55(d,J=7.3 Hz, 1H), 11.99(s, 1H). 2-[(2,4-dioxo-2,3- (CD₃SO₂CD₃) δ 2.81(s,6H), 5.54(s, 2H), dihydro[1,3]oxazolo[4,5- 6.71(d, J=7.3 Hz, 1H),6.81(d, J=7.3 Hz, c]pyridin-5(4H)-yl)methyl]- 1H), 7.49-7.61(m, 2H),7.69(d, J=7.3 Hz, N,N- 1H), 7.85(d, J=7.3 Hz, 1H), 12.05(br. s,dimethylbenzenesulfonamide 1H). 5-(2,6-dimethoxybenzyl)-3,5- (CD₃SO₂CD₃)δ 3.76(s, 6H), 5.07(s, 2H), dihydro[1,3]oxazolo[4,5- 6.43(d, J=7.7 Hz,1H), 6.73(d, J=8.4 Hz, c]pyridine-2,4-dione 2H), 7.00(d, J=7.7 Hz, 1H),7.37(t, J=8.4 Hz, 1H), 11.92(br. s, 1H). 5-[2- (CD₃SO₂CD₃) δ 5.27(s,2H), 6.65(d, J=7.3 Hz, (trifluoromethoxy)benzyl]-3,5- 1H), 7.08(dd,J=7.3, 1.4 Hz, 1H), dihydro[1,3]oxazolo[4,5- 7.30-7.49(m, 3H), 7.63(d,J=7.3 Hz, 1H), c]pyridine-2,4-dione 11.99(br. s, 1H).5-(2-chlorobenzyl)-6,7- (CD₃SO₂CD₃) δ 2.12(s, 3H), 2.19(s, 3H),dimethyl-3,5- 5.40(s, 2H), 6.59(d, J=6.6 Hz, 1H),dihydro[1,3]oxazolo[4,5- 7.25-7.34(m, 2H), 7.52(d, J=7.7 Hz, 1H),c]pyridine-2,4-dione 11.91(br. s, 1H). 5-[2-chloro-5 (CD₃SO₂CD₃) δ3.20(s, 3H), 5.35(s, 2H), (methylsulfonyl)benzyl]-3,5- 6.70(d, J=7.3 Hz,1H), 7.55(m, 1H), dihydro[1,3]oxazolo[4,5- 7.69(m, 1H), 7 90(m, 2H),12.04(br. s, 1H). c]pyridine-2,4-dione 5-(4-chloro-2-methoxybenzyl)-(CD₃SO₂CD₃) δ 3.86(s, 3H), 5.09(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5-6.60(d, J=7.3 Hz, 1H), 6.90-6.98(m, 2H), c]pyridine-2,4-dione 7.12(d,J=2.2 Hz, 1H), 7.59(d, J=7.3 Hz, 1H), 11.95(br. s, 1H).5-(2-chlorobenzyl)- (CD₃SO₂CD₃) δ 1.34(m, 2H), 1.56(m, 2H),5,6,7,8,9,10-hexahydro-2H- 1.69(m, 2H), 2.70(m, 4H), 5.45(s, 2H),cyclohepta[b][1,3]oxazolo[5,4- 6.69(d, J=6.6 Hz, 1H), 7.24-7.35(m, 2H),d]pyridine-2,4(3H)-dione 7.52(d, J=7.7 Hz, 1H), 11.91(br. s, 1H). 5-[2-(CD₃SO₂CD₃) δ 5.21(s, 2H), 6.64(d, J=7.3 Hz,(difluoromethoxy)benzyl]-3,5- 1H), 7.02(d, J=7.3 Hz, 1H),dihydro[1,3]oxazolo[4,5- 7.20-7.25(m, 2H), 7.27(t, J=74.0 Hz, 1H),7.62(d, J=7.3 Hz, c]pyridine-2,4-dione 1H), 12.00(br. s, 1H).7-methyl-5-[(1R)-1- (CD₃SO₂CD₃) δ 1.72(d, J=7.3 Hz, 3H),phenylethyl]-3,5- 2.07(s, 3H), 6.27(q, J=7.3 Hz, 1H),dihydro[1,3]oxazolo[4,5- 7.27-7.40(m, 6H), 11.95(br. s, 1H).c]pyridine-2,4-dione 5-(4-chlorobenzyl)-7-propyl- (CD₃SO₂CD₃) δ 0.89(t,J=7.3 Hz, 3H), 3,5-dihydro[1,3]oxazolo[4,5- 1.54(m, 2H), 2.44(t, J=7.7Hz, 2H), 5.15(s, 2H), c]pyridine-2,4-dione 7.30(d, J=8.4 Hz, 2H),7.39(d, J=8.4 Hz, 2H), 7.57(s, 1H), 11.97(br. s, 1H).5-[2-(methylsulfonyl)benzyl]- (CD₃SO₂CD₃) δ 3.43(s, 3H), 5.60(s, 2H),3,5-dihydro[1,3]oxazolo[4,5- 6.75(d, J=7.3 Hz, 1H), 7.49-7.61(m, 2H),c]pyridine-2,4-dione 7.65-7.70(m, 2H) 7.89-7.91(m, 1H), 12.02(br. s,1H). 5-(2,6-dimethylbenzyl)-3,5- (CD₃SO₂CD₃) δ 2.21(s, 6H), 5.16(s, 2H),dihydro[1,3]oxazolo[4,5- 6.47(d, J=7.3 Hz, 1H), 6.80(d, J=7.3 Hz,c]pyridine-2,4-dione 1H), 7.09-7.22(m, 3H), 12.00(br. s, 1H).3-chloro-2-[(2,4-dioxo-2,3- (CD₃SO₂CD₃) δ 5.38(s, 2H), 6.61(d, 7.4 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.55(t, J=8.0 Hz, 1H), 7.62(d, J=7.4 Hz,c]pyridin-5(4H)- 1H), 7.82(d, J=8.0 Hz, 1H), 7.87(d, J=8.0 Hz,yl)methyl]benzonitrile 1H), 11.96(br. s, 1H).5-(2-chloro-6-methylbenzyl)- (CD₃SO₂CD₃) δ 2.06(s, 3H), 2.09(s, 3H),6,7-dimethyl-3,5- 2.10(s, 3H), 5.58(s, 2H), 7.13(d, J=7.7 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.20(t, J=7.7 Hz, 2H), 7.27(d, J=7.7 Hz,c]pyridine-2,4-dione 1H), 11.84(br. s, 1H). 2-[(2,4-dioxo-2,3-(CD₃SO₂CD₃) δ 5.40(s, 2H), 6.70(d, J=7.4 Hz, dihydro[1,3]oxazolo[4,5-1H), 7.11(d, J=7.7 Hz, 1H), 7.50(t, J=7.7 Hz, c]pyridin-5(4H)- 1H),7.66(td, J=7.7, 1.1 Hz, 1H), yl)methyl]benzonitrile 7.74(d, J=7.4 Hz,1H), 7.88(dd, J=7.7, 1.1 Hz, 1H), 12.01(br. s, 1H).5-(2-chloro-6-methoxybenzyl)- (CD₃SO₂CD₃) δ 2.01(s, 3H), 3.81(s, 3H),7-methyl-3,5- 5.21(s, 2H), 6.86(s, 1H), 7.11(m, 2H),dihydro[1,3]oxazolo[4,5- 7.41(t, J=8.2 Hz, 1H), 11.96(br. s, 1H).c]pyridine-2,4-dione 5-[3-(methylthio)benzyl]-3,5- (CD₃SO₂CD₃) δ 2.45(s,3H), 5.16(s, 2H), dihydro[1,3]oxazolo[4,5- 6.61(d, J=7.3 Hz, 1H),7.04(d, J=7.3 Hz, c]pyridine-2,4-dione 1H), 7.16-7.34(m, 3H), 7.73(d,J=7.3 Hz, 1H), 11.97(br. s, 1H). 5-(2-chlorobenzyl)-7- (CD₃SO₂CD₃) δ0.70(m, 2H), 0.87(m, 2H), cyclopropyl-3,5- 1.79(m, 1H), 5.22(s, 2H),6.79(d, J=7.3 Hz, dihydro[1,3]oxazolo[4,5- 1H), 7.31(m, 1H), 7.45(s,1H), 7.50(d, J=7.7 Hz, c]pyridine-2,4-dione 1H), 12.01(br. s, 1H).5-(3-chlorobenzyl)-7-methyl- (CD₃SO₂CD₃) δ 2.09(d, J=1.1 Hz, 3H),3,5-dihydro[1,3]oxazolo[4,5- 5.15(s, 2H), 7.26(m, 1H), 7.33-7.41(m, 3H),c]pyridine-2,4-dione 7.59(q, J=1.1 Hz, 1H), 11.97(br. s, 1H).5-(2,6-dichlorobenzyl)-7- (CD₃SO₂CD₃) δ 2.03(d, J=1.1 Hz, 3H),methyl-3,5- 5.36(s, 2H), 6.87(q, J=1.1 Hz, 1H), 7.46(dd, J=8.8,dihydro[1,3]oxazolo[4,5- 7.4 Hz, 1H), 7.56(d, J=7.4 Hz, 1H),c]pyridine-2,4-dione 7.57(d, J=8.8 Hz, 1H), 11.99(br. s, 1H).7-methyl-5-(4-methylbenzyl)- (CD₃SO₂CD₃) δ 2.07(s, 3H), 2.27(s, 3H),3,5-dihydro[1,3]oxazolo[4,5- 5.10(s, 2H), 7.08-7.23(m, 4H), 7.52(s, 1H),c]pyridine-2,4-dione 11.95(br. s, 1H). 5-(3,5-dimethoxybenzyl)-7-(CD₃SO₂CD₃) δ 2.09(s, 3H), 3.71(s, 6H), methyl-3,5- 5.06(s, 2H), 6.42(t,J=2.2 Hz, 1H), 6.46(d, dihydro[1,3]oxazolo[4,5- J=2.2 Hz, 2H), 7.51(s,1H), 11.96(br. s, c]pyridine-2,4-dione 1H). 5-(2,6-difluorobenzyl)-7-(CD₃SO₂CD₃) δ 2.09(d, J=1.1 Hz, 3H), methyl-3,5- 5.21(s, 2H),7.04-7.13(m, 2H), 7.38-7.47(m, 2H), dihydro[1,3]oxazolo[4,5- 11.91(br.s, 1H). c]pyridine-2,4-dione 5-[3-(methylsulfonyl)benzyl]- (CD₃SO₂CD₃) δ3.20(s, 3H), 5.31(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5- 6.66(d, J=7.3 Hz,1H), 7.5-7.7(m, 2H), c]pyridine-2,4-dione 7.81(d, J=7.3 Hz, 1H),7.83-7.96(m, 2H), 11.99(br. s, 1H). 5-(2-chloro-6-ethoxybenzyl)-(CD₃SO₂CD₃) δ 1.25(t, J=7.0 Hz, 3H), 3,5-dihydro[1,3]oxazolo[4,5-4.05(q, J=7.0 Hz, 2H), 5.25(s, 2H), 6.49(d, J=7.3 Hz,c]pyridine-2,4-dione 1H), 7.06(d, J=8.4 Hz, 1H), 7.10(d, J=8.1 Hz, 1H),7.12(d, J=7.3 Hz, 1H), 7.37(dd, J=8.4, 8.1 Hz, 1H), 11.95(br. s, 1H).5-(2-chloro-6-ethoxybenzyl)-7- (CD₃SO₂CD₃) δ 1.25(t, J=7.0 Hz, 3H),methyl-3,5- 2.02(s, 3H), 4.04(q, J=7.0 Hz, 2H), 5.23(s, 2H),dihydro[1,3]oxazolo[4,5- 6.97(s, 1H), 7.04(d, J=8.4 Hz, 1H), 7.09(d,c]pyridine-2,4-dione J=8.0 Hz, 1H), 7.36(dd, J=8.4, 8.0 Hz, 1H),11.93(br. s, 1H). 5-(2-fluoro-6-methoxybenzyl)- (CD₃SO₂CD₃) δ 2.05(s,3H), 3.82(s, 3H), 7-methyl-3,5- 5.12(s, 2H), 6.82(dd, J=9.5, 8,4 Hz,1H), dihydro[1,3]oxazolo[4,5- 6.91(d, J=8.4 Hz, 1H), 7.18(s, 1H),c]pyridine-2,4-dione 7.37(td, J=8.4, 6.6 Hz, 1H), 11.89(br. s, 1H).5-(2-chloro-6-methoxybenzyl)- (CD₃SO₂CD₃) δ 0.82(t, J=7.3 Hz, 3H),7-propyl-3,5- 1.47(sextet, J=7.3 Hz, 2H), 2.38(t, J=7.3 Hz,dihydro[1,3]oxazolo[4,5- 2H), 3.80(s, 3H), 5.21(s, 2H), 6.89(s, 1H),c]pyridine-2,4-dione 7.08-7.13(m, 2H), 7.40(t, J=8.3 Hz, 1H), 11.93(br.s, 1H). 5-(5-chloro-2-fluorobenzyl)-7- (CD₃SO₂CD₃) δ 2.10(s, 3H),5.18(s, 2H), methyl-3,5- 7.20(dd, J=6.6, 3.0 Hz, 1H), 7.29(dd, J=9.6,dihydro[1,3]oxazolo[4,5- 8.8 Hz, 1H), 7.42(ddd, J=8.8, 4.4, 3.0 Hz,c]pyridine-2,4-dione 1H), 7.51(s, 1H), 11.96(br. s, 1H).5-(2-chlorobenzyl)-7- (CD₃SO₂CD₃) δ 1.23(d, J=7.0 Hz, 6H),isopropyl-3,5- 2.92(m, 1H), 5.25(s, 2H), 6.83(dd, J=7.4, 2.2 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.27-7.35(m, 2H), 7.49(s, 1H),c]pyridine-2,4-dione 7.51(dd, J=7.3, 1.8 Hz, 1H), 12.01(br. s, 1H).5-(5-fluoro-2-methylbenzyl)-7- (CD₃SO₂CD₃) δ 2.10(d, J=1.1 Hz, 3H),methyl-3,5- 2.30(s, 3H), 5.13(s, 2H), 6.55(dd, J=9.9, 2.6 Hz,dihydro[1,3]oxazolo[4,5- 1H), 7.01(td, J=8.4, 2.6 Hz, 1H), 7.25(dd,J=8.4, c]pyridine-2,4-dione 5.9 Hz, 1H), 7.42(q, 1.1 Hz, 1H), 11.99(br.s, 1H). 7-methyl-5-[(1S)-1- (CD₃SO₂CD₃) δ 1.72(d, J=7.3 Hz, 3H),phenylethyl]-3,5- 2.07(s, 3H), 6.27(q, J=7.3 Hz, 1H),dihydro[1,3]oxazolo[4,5- 7.27-7.40(m, 6H), 11.95(br. s, 1H).c]pyridine-2,4-dione 5-(2-chloro-5- (CD₃SO₂CD₃) δ 1.20(d, J=6.0 Hz, 6H),isopropoxybenzyl)-7-methyl- 2.11(s, 3H), 4.50(m, 1H), 5.16(s, 2H),6.34(d, J=3.0 Hz, 3,5-dihydro[1,3]oxazolo[4,5- 1H), 6.91(dd, J=8.8, 3.0Hz, 1H), c]pyridine-2,4-dione 7.38(d, J=8.8 Hz, 1H), 7.47(s, 1H),12.01(br. s, 1H). 5-(5-acetyl-2-methoxybenzyl)- (CD₃SO₂CD₃) δ 2.47(s,3H), 3.93(s, 3H), 3,5-dihydro[1,3]oxazolo[4,5- 5.16(s, 2H), 6.62(d,J=7.3 Hz, 1H), 7.16(d, c]pyridine-2,4-dione J=8.4 Hz, 1H), 7.59(d, J=2.2Hz, 1H), 7.63(d, J=7.3 Hz, 1H), 7.97(dd, J=8.4, 2.2 Hz, 1H), 11.96(br.s, 1H). 5-(2-chlorobenzyl)-7-methyl- (CD₃SO₂CD₃) δ 2.29(s, 3H), 5.39(s,2H), 3,5-dihydro[1,3]oxazolo[4,5- 7.00(d, J=7.4 Hz, 1H), 7.26-7.37(m,2H), d]pyridazine-2,4-dione 7.51(d, J=7.7 Hz, 1H), 12.80(br. s, 1H).5-[2-fluoro-6- (CD₃SO₂CD₃) δ 2.04(s, 3H), 5.33(s, 2H),(trifluoromethyl)benzyl]-7- 7.05(s, 1H), 7.51-7.72(m, 3H), 11.98(br. s,methyl-3,5- 1H). dihydro[1,3]oxazolo[4,5- c]pyridine-2,4-dione5-(2-chloro-6-methylbenzyl)- (CD₃SO₂CD₃) δ 2.02(m, 2H), 2.21(s, 3H),5,6,7,8-tetrahydro-2H- 2.64-2.80(m, 4H), 5.42(s, 2H), 7.05-7.33(m,cyclopenta[b][1,3]oxazolo[5,4- 3H), 11.81(br. s, 1H).d]pyridine-2,4(3H)-dione 5-(2-chloro-6-ethoxybenzyl)-7- (CD₃SO₂CD₃) δ1.08(t, J=7.7 Hz, 3H), ethyl-3,5- 1.25(t, J=7.0 Hz, 3H), 2.44(q, J=7.7Hz, 2H), dihydro[1,3]oxazolo[4,5- 4.05(q, J=7.0 Hz, 2H), 5.23(s, 2H),6.99(s, c]pyridine-2,4-dione 1H), 7.05(d, J=8.4 Hz, 1H), 7.09(d, J=8.1Hz, 1H), 7.36(dd, J=8.4, 8.1 Hz, 1H), 11.93(br. s, 1H).5-(2-chloro-6-propoxybenzyl)- (CD₃SO₂CD₃) δ 0.88(t, J=7.3 Hz, 3H),7-methyl-3,5- 1.66(m, 2H), 2.01(d, J=1.1 Hz, 3H), 3.95(t, J=6.2 Hz,dihydro[1,3]oxazolo[4,5- 2H), 5.24(s, 2H), 6.91(q, J=1.1 Hz,c]pyridine-2,4-dione 1H), 7.03(d, J=8.4 Hz, 1H), 7.10(d, J=8.1 Hz, 1H),7.37(dd, J=8.4, 8.1 Hz, 1H), 11.95(br. s, 1H). 5-(2-chloro-6-(CD₃SO₂CD₃) δ 0.89(d, J=7.0 Hz, 6H), isobutoxybenzyl)-7-methyl- 1.95(m,1H), 2.00(s, 3H), 3.79(d, J=6.2, 2H), 3,5-dihydro[1,3]oxazolo[4,5-5.25(s, 2H), 6.85(s, 1H), 7.06(d, J=8.4 Hz, c]pyridine-2,4-dione 1H),7.11(d, J=8.1 Hz, 1H), 7.38(dd, J=8.4, 8.1 Hz, 1H), 11.97(br. s, 1H).5-(2-chloro-6-ethoxybenzyl)- (CD₃SO₂CD₃) δ 1.10(t, J=7.0 Hz, 3H),5,6,7,8-tetrahydro-2H- 2.06(m, 2H), 2.70-2.92(m, 4H), 3.90(q, J=7.0 Hz,cyclopenta[b][1,3]oxazolo[5,4- 2H), 5.33(s, 2H), 6.93(d, J=8.4 Hz,d]pyridine-2,4(3H)-dione 1H), 7.03(d, J=8.1 Hz, 1H), 7.26(dd, J=8.4, 8.1Hz, 1H), 11.75(br. s, 1H). 5-(2-chloro-6- (CD₃SO₂CD₃) δ 1.16(d, J=6.2Hz, 6H), isopropoxybenzyl)-7-methyl- 2.02(s, 3H), 4.67(m, 1H), 5.21(s,2H), 6.94(s, 3,5-dihydro[1,3]oxazolo[4,5- 1H), 7.07(d, J=8.0 Hz, 2H),7.34(t, J=8.0 Hz, c]pyridine-2,4-dione 1H), 11.93(br. s, 1H).5-[2-chloro-6-(2,2,2- (CD₃SO₂CD₃) δ 2.01(s, 3H), 4.82(q, J=8.8 Hz,trifluoroethoxy)benzyl]-7- 2H), 5.24(s, 2H), 6.94(s, 1H), 7.19(d, J=8.4Hz, methyl-3,5- 1H), 7.22(d, J=8.1 Hz, 1H), dihydro[1,3]oxazolo[4,5-7.43(dd, J=8.4, 8.1 Hz, 1H), 11.92(br. s, 1H). c]pyridine-2,4-dione5-(2-chloro-6-ethoxybenzyl)-7- (CD₃SO₂CD₃) δ 1.19(t, J=7.0 Hz, 3H),methyl-3,5- 2.19(s, 3H), 3.99(q, J=7.0 Hz, 2H), 5.41(s, 2H),dihydro[1,3]oxazolo[4,5- 6.98(d, J=8.4 Hz, 1H), 7.05(d, J=8.0 Hz,d]pyridazine-2,4-dione 1H), 7.30(dd, J=8.4, 8.0 Hz, 1H), 12.70(br. s,1H). 5-[2-chloro-6-(2- (CD₃SO₂CD₃) δ 2.06(m, 2H), 2.74-2.90(m,methoxyethoxy)benzyl]- 4H), 3.20(s, 3H), 3.47(t, J=4.4 Hz, 2H),5,6,7,8-tetrahydro-2H- 4.01(t, J=4.4 Hz, 2H), 5.33(s, 2H), 6.98(d,cyclopenta[b][1,3]oxazolo[5,4- J=8.0 Hz, 1H), 7.04(d, J=8.0 Hz, 1H),d]pyridine-2,4(3H)-dione 7.27(t, J=8.0 Hz, 1H), (br. s, 1H).5-(2-chloro-6-ethoxybenzyl)- (CD₃SO₂CD₃) δ 1.03(t, J=7.0 Hz, 3H),6,7-dimethyl-3,5- 2.06(s, 3H), 2.22(s, 3H), 3.84(q, J=7.0 Hz, 2H),dihydro[1,3]oxazolo[4,5- 5.48(s, 2H), 6.92(d, 8.4 Hz, 1H), 7.03(d, J=8.1Hz, c]pyridine-2,4-dione 1H), 7.24(dd, J=8.4, 8.1 Hz, 1H), 11.76(br.s,1H). 5-(2-chloro-6-ethoxybenzyl)-7- (CD₃SO₂CD₃) δ 1.06(m, 6H), 2.24(s,3H), ethyl-6-methyl-3,5- 2.48-2.56(m overlapping DMSO, 2H),dihydro[1,3]oxazolo[4,5- 3.85(q, J=7.0 Hz, 2H), 5.48(s, 2H), 6.92(d, 8.4Hz, c]pyridine-2,4-dione 1H), 7.03(d, J=8.1 Hz, 1H), 7.24(dd, J=8.4, 8.1Hz, 1H), 11.77(br.s, 1H). 5-(2-chlorobenzyl)-7-ethyl-3,5- (CD₃SO₂CD₃) δ1.18(t, J=7.5 Hz, 3H), dihydro[1,3]oxazolo[4,5- 2.70(q, J=7.5 Hz, 2H),5.38(s, 2H), 7.0-7.6(m, d]pyridazine-2,4-dione 4H), 12.77(br. s, 1H).5-(2-chloro-6-ethoxybenzyl)-7- (CD₃SO₂CD₃) δ 0.82(t, J=7.3 Hz, 3H),propyl-3,5- 1.24(t, J=7.0 Hz, 3H), 1.48(m, 2H), 2.37(t, J=7.3 Hz,dihydro[1,3]oxazolo[4,5- 2H), 4.05(q, J=7.0 Hz, 2H), 5.23(s,c]pyridine-2,4-dione 2H), 6.93(s, 1H), 7.05(d, J=8.4 Hz, 1H), 7.09(d,J=8.1 Hz, 1H), 7.36(dd, J=8.4, 8.1 Hz, 1H), 11.94(br. s, 1H).5-(2-chloro-6-ethoxybenzyl)-7- (CD₃SO₂CD₃) δ 0.55(m, 2H), 0.81(m, 2H),cyclopropyl-3,5- 1.26(t, J=7.0 Hz, 3H), 1.72(m, 1H), 4.05(q,dihydro[1,3]oxazolo[4,5- J=7.0 Hz, 2H), 5.22(s, 2H), 6.95(s, 1H),c]pyridine-2,4-dione 7.05(d, J=8.4 Hz, 1H), 7.09(d, J=8.1 Hz, 1H),7.36(dd, J=8.4, 8.1 Hz, 1H), 11.93(br. s, 1H).5-(2-chloro-5-propoxybenzyl)- (CD₃SO₂CD₃) δ 0.92(t, J=7.3 Hz, 3H),7-methyl-3,5- 1.66(m, 2H), 2.10(s, 3H), 3.85(m, 2H), 5.17(s,dihydro[1,3]oxazolo[4,5- 2H), 6.41(d, J=3.3 Hz, 1H), 6.91(dd, J=8.8,c]pyridine-2,4-dione 3.3 Hz, 1H), 7.39(d, J=8.8 Hz, 1H), 7.45(s, 1H),12.00(br. s, 1H). 5-(2-chloro-5-methoxybenzyl)- (CD₃SO₂CD₃) δ 2.10(s,3H), 3.9(s, 3H), 7-methyl-3,5- 5.18(s, 2H), 6.42(d, J=3.0 Hz, 1H),6.93(dd, J=8.8, dihydro[1,3]oxazolo[4,5- 3.0 Hz, 1H), 7.42(d, J=8.8 Hz,1H), c]pyridine-2,4-dione 7.44(s, 1H), 12.00(br. s, 1H).5-(2-chloro-6-ethoxybenzyl)-6- (CD₃SO₂CD₃) δ 1.07(t, J=7.0 Hz, 3H),methyl-3,5- 2.32(s, 3H), 3.87(q, J=7.0 Hz, 2H), 5.42(s, 2H),dihydro[1,3]oxazolo[4,5- 6.44(s, 1H), 6.92(d, J=8.4 Hz, 1H), 7.03(d,c]pyridine-2,4-dione J=8.1 Hz, 1H), 7.24(dd, J=8.4, 8.1 Hz, 1H),11.74(br. s, 1H). 5-(2-chloro-5-ethoxybenzyl)-7- (CD₃SO₂CD₃) δ 1.26(t,J=7.0 Hz, 3H), methyl-3,5- 2.10(s, 3H), 3.94(q, J=7.0 Hz, 2H), 5.17(s,2H), dihydro[1,3]oxazolo[4,5- 6.38(d, J=2.9 Hz, 1H), 6.91(dd, J=8.8, 2.9Hz, c]pyridine-2,4-dione 1H), 7.39(d, J=8.8 Hz, 1H), 7.44(s, 1H),11.99(br. s, 1H). 5-[2-chloro-5-(piperidin-1- (CD₃SO₂CD₃) δ 1.35(m, 2H),1.47(m, 4H), ylsulfonyl)benzyl]-7-methyl- 2.10(s, 3H), 2.81(m, 4H),5.30(s, 2H), 3,5-dihydro[1,3]oxazolo[4,5- 7.18(d, J=2.2 Hz, 1H), 7.57(s,1H), 7.67(dd, J=8.4, c]pyridine-2,4-dione 2.2 Hz, 1H), 7.78(d, J=8.4 Hz,1H), 12.07(br. s, 1H). 5-[2-chloro-5-(pyrrolidin-1- (CD₃SO₂CD₃) δ1.62(m, 4H), 2.11(s, 3H), ylsulfonyl)benzyl]-7-methyl- 3.05(m, 4H),5.30(s, 2H), 7.30(s, 1H), 3,5-dihydro[1,3]oxazolo[4,5- 7.57(s, 1H),7.75-7.82(m, 2H), 12.08(br. s, 1H). c]pyridine-2,4-dione 5-[2-chloro-6-(CD₃SO₂CD₃) δ 1.22(m, 2H), 1.51(m, 4H), (cyclopentylmethoxy)benzyl]-1.68(m, 2H), 2.00(s, 3H), 2.20(m, 1H), 7-methyl-3,5- 3.89(d, J=7.0 Hz,2H), 5.24(s, 2H), 6.86(s, 1H), dihydro[1,3]oxazolo[4,5- 7.07(d, J=8.4Hz, 1H), 7.11(d, J=8.1 Hz, c]pyridine-2,4-dione 1H), 7.37(dd, J=8.4, 8.1Hz, 1H), 11.97(br. s, 1H). 5-[2-(benzyloxy)-6- (CD₃SO₂CD₃) δ 1.90(s,3H), 5.15(s, 2H), chlorobenzyl]-7-methyl-3,5- 5.25(s, 2H), 6.84(s, 1H),7.13(d, J=8.1 Hz, dihydro[1,3]oxazolo[4,5- 1H), 7.19(d, J=7.7 Hz, 1H),7.30-7.37(m, c]pyridine-2,4-dione 5H), 7.39(dd, J=8.1, 7.7 Hz, 1H),11.91(br. s, 1H). 5-(2,3-dichloro-6- (CD₃SO₂CD₃) δ 1.10(t, J=7.0 Hz,3H), ethoxybenzyl)-5,6,7,8- 2.09(m, 2H) 2.80(m, 2H), 2.89(m, 2H),3.92(q, J=7.0 Hz, tetrahydro-2H- 2H), 5.33(s, 2H), 6.98(d, J=8.8 Hz,cyclopenta[b][1,3]oxazolo[5,4- 1H), 7.50(d, J=8.8 Hz, 1H), 11.71(br. s,d]pyridine-2,4(3H)-dione 1H). 5-[2-chloro-5- (CD₃SO₂CD₃) δ 2.11(s, 3H),5.29(s, 2H), (trifluoromethyl)benzyl]-7- 7.34(s, 1H), 7.54(s, 1H),7.72-7.79(m, 2H), methyl-3,5- 12.00(br. s, 1H). dihydro[1,3]oxazolo[4,5-c]pyridine-2,4-dione 5-(2-chloro-5-fluorobenzyl)-7- (CD₃SO₂CD₃) δ2.11(s, 3H), 5.20(s, 2H), methyl-3,5- 6.71(dd, J=9.4, 2.9 Hz, 1H),7.22(td, J=8.4, dihydro[1,3]oxazolo[4,5- 2.9 Hz, 1H), 7.49(s, 1H),7.57(dd, J=8.4, c]pyridine-2,4-dione 5.2 Hz, 1H), 11.99(br. s, 1H).

EXAMPLE 42

A procedure in which a 26-amino acid peptide containing the CS1 sequenceof fibronectin with an N-terminal Cys (CDELPQLVTLPHPNLHGPEILDVPST) wascoupled to maleimide activated ovalbumin was used to determine theefficacy of the compounds synthesized. Bovine serum albumin (BSA) andCS1 conjugated ovalbumin were coated onto 96-well polystyrene plates at0.5 μg/ml in TBS (50 mM TRIS, pH 7.5; 150 mM NaCl) at 4° C. for 16hours. The plates were washed three times with TBS and blocked with TBScontaining 3% BSA at room temperature for 4 hours. Blocked plates werewashed three times in binding buffer (TBS; 1 mM MgCl₂; 1 mM CaCl₂; 1 mMMnCl₂) prior to assay. Ramos cells fluorescently labeled with calcein AMwere resuspended in binding buffer (1 cells/ml) and diluted 1:2 withsame buffer with or without compound. 100 μM of compound was added. Thecells were added immediately to the wells (2.5×10⁵ cells/well) andincubated for 30 minutes at 37° C. Following three washes with bindingbuffer, adherent cells were lysed and quantitated using a fluorometer.The results are shown in Tables 2-7. IC₅₀ is defined as the doserequired to give 50% inhibition, measured in μM for Tables 2 and 4. Thelower the IC₅₀ value and the greater the percentage of inhibition, themore efficient the compound is at prevention of cell adhesion.

TABLE 2 Mass Name IC₅₀ Spectral Data (m/z)(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2- 0.2 Calc'd (M − H)⁻= 444.12; thienylmethyl)hexahydro-3- Found (M − H)⁻ = 444.08pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2- 15 Calc'd (M − H)⁻= 430.11; thienylmethyl)tetrahydro-1H-pyrrol-3- Found (M − H)⁻ = 430.06yl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3R)-2-oxo-1-(2- 2 Calc'd (M − H)⁻ =444.12; thienylmethyl)hexahydro-3- Found (M − H)⁻ = 444.05pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-(2- 0.9 Calc'd (M − H)⁻ =440.09; thienylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 439.98pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-({[((3S)-2-oxo-1-{4-[(2- 0.0003 Calc'd(M − H)⁻ = 586.23; toluidinocarbonyl)amino]benzyl}hexahydro-3- Found (M− H)⁻ = 586.17 pyridinyl)amino]carbonyl}amino)propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1-{4-[(2- 0.001 Calc'd (M −H)⁻ = 582.20; toluidinocarbonyl)amino]benzyl}-1,2-dihydro-3- Found (M −H)⁻ = 582.20 pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-({[((3S)-1-{4-[(2- nd ndmethylbenzyl)amino]benzyl}-2-oxohexahydro-pyridinyl)amino]carbonyl}amino)propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2-oxo-1-(2- 20 Calculated (M −H)⁻ = 496.15; thienylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 496.10pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[(3S)-2-oxo-1-(2- 0.015 Calculated (M− H)⁻ = 458.13; thienylmethyl)azepanyl]amino}carbonyl)amino]propanoicFound (M − H)⁻ = 458.09 acid

TABLE 3 IC₅₀ Compound (nM) Mass Spectral Data(3S)-3-[({[2-methyl-4-(2-methylpropyl)-6-oxo-1- 10 Calculated (M − H)⁻ =475.23 m/z; (phenylmethyl)-1,6-dihydro-5- Found (M − H)⁻ = 475.02 m/z.pyrimidinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1- 10 Calculated (M − H)⁻ =476.18 m/z; (phenylmethyl)-4-propyl-1,2-dihydro-3- Found (M − H)⁻ =475.99 m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-({[9-oxo-8- 4000 Calculated (M − H)⁻ =488.18 m/z; (phenylmethyl)-2,3,4,5,8,9-hexahydro-1H- Found (M − H)⁻ =488.19 m/z. pyrido[3,4-b]azepin-1- yl]carbonyl}amino)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-ethyl-2- 10 Calculated (M − H)⁻= 466.15 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 465.95 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4- 4 Calculated (M − H)⁻ =480.17 m/z; propyl-1,2-dihydro-3- Found (M − H)⁻ = 480.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl- 5 Calculated (M + H)⁺ =454.15 m/z; 2-oxo-1,2-dihydro-3- Found (M + H)⁺ = 454.09 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({6-methyl-2-oxo-1-(phenylmethyl)-4- 5 Calculated (M − H)⁻ =524.22 m/z; [(phenylmethyl)oxy]-1,2-dihydro-3- Found (M − H)⁻ = 524.02m/z. pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2,4- 10 Calculated (M − H)⁻ =467.15 m/z; dimethyl-6-oxo-1,6-dihydro-5- Found (M − H)⁻ = 467.00 m/z.pyrimidinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2,4-dichlorophenyl)methyl]-4- 30 Calculated (M − H)⁻ =486.10 m/z; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 485.95 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]- 10 Calculated (M − H)⁻ =467.15 m/z; 6-methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 467.14 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4- 20 Calculated (M − H)⁻ = 468.13m/z; (methyloxy)-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 467.97 m/z.pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-chloro-1-[(2-chlorophenyl)methyl]- 20 Calculated (M − H)⁻ =472.08 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 471.91 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl- 15 Calculated (M − H)⁻ =482.15 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 481.93 m/z.pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl- 3 Calculated (M + H)⁺ =470.15 m/z; 2-oxo-1,2-dihydro-3- Found (M + H)⁺ = 470.01 m/z.pyridinyl}amino)carbonyl]amino}-3-[4- (methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl- 10 Calculated (M + H)⁺ =468.17 m/z; 2-oxo-1,2-dihydro-3- Found (M + H)⁺ = 468.05 m/z.pyridinyl}amino)carbonyl]amino}-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-{[({4-amino-1-[(2-chlorophenyl)methyl]- 10 Calculated (M − H)⁻ =453.13 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 453.01 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-fluoro- 15 Calculated (M − H)⁻ =456.12 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 455.94 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4- 20 Calculated (M − H)⁻ =529.16 m/z; (phenylamino)-1,2-dihydro-3- Found (M − H)⁻ = 529.02 m/z.pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4- 15 Calculated (M − H)⁻ =530.16 m/z; (2-pyridinylamino)-1,2-dihydro-3- Found (M − H)⁻ = 529.99m/z. pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 10 Calculated (M − H)⁻ = 454.11m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 454.05 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4- 15 Calculated (M − H)⁻ =544.17 m/z; [(2-pyridinylmethyl)amino]-1,2-dihydro-3- Found (M − H)⁻ =544.03 m/z. pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4- 20 Calculated (M −H)⁻ = 544.17 m/z; [(3-pyridinylmethyl)amino]-1,2-dihydro-3- Found (M −H)⁻ = 544.02 m/z. pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-(1,4- 1 Calculated (M − H)⁻ =523.17 m/z; oxazinan-4-yl)-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 523.02m/z. pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-[(2-chlorophenyl)methyl]-2-oxo-4- 10 Calculated (M − H)⁻ =495.18 m/z; (propylamino)-1,2-dihydro-3- Found (M − H)⁻ = 495.04 m/z.pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-fluorophenyl)methyl]-4-methyl- 20 Calculated (M − H)⁻ =436.17 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 435.99 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2,6-dichlorophenyl)methyl]-4- 20 Calculated (M − H)⁻ =486.10 m/z; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 485.95 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3R)-3-{[({1-[(2-chlorophenyl)methyl]-4-methyl- 300 Calculated (M − H)⁻= 376.11 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 376.00 m/z.pyridinyl}amino)carbonyl]amino}butanoic acid(3S)-3-{[({1-[(2-bromophenyl)methyl]-4-methyl- 10 Calculated (M − H)⁻ =496.09 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 495.87 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[4-methyl-2-oxo-1-(phenylmethyl)-1,2- 30 Calculated (M − H)⁻ =418.17 m/z; dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4- Found (M −H)⁻ = 417.96 m/z. methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 8 Calculated (M − H)⁻ = 484.12m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 484.03 m/z.pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4- 10 Calculated (M − H)⁻ =514.15 m/z; phenyl-1,2-dihydro-3- Found (M − H)⁻ = 514.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-bromo-1-[(2-chlorophenyl)methyl]- 20 Calculated (M − H)⁻ =516.03 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 515.90 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(2- 20 Calculated (M − H)⁻ =484.09 m/z; chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M − H)⁻ =484.03 m/z. dihydro-3- pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(2-{[2- 2 Calculated (M − H)⁻ =556.18 m/z; (methyloxy)ethyl]oxy}ethyl)oxy]-2-oxo-1,2- Found (M − H)⁻ =556.03 m/z. dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-15 Calculated (M − H)⁻ = 468.13 m/z;hydroxy-6-methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 468.05 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(1,1- 3 Calculated (M − H)⁻ =509.20 m/z; dimethylethyl)amino]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =509.06 m/z. pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 10 Calculated (M − H)⁻ =440.10 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 440.04 m/z.pyridinyl}amino)carbonyl]amino}-3- phenylpropanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[4- 3 Calculated (M − H)⁻ =536.20 m/z; methyltetrahydro-1(2H)-pyrazinyl]-2-oxo-1,2- Found (M − H)⁻= 536.12 m/z. dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-5 Calculated (M − H)⁻ = 470.11 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found(M − H)⁻ = 470.05 m/z. pyridinyl}amino)carbonyl]amino}-3-[4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 20 Calculated (M − H)⁻ = 530.13m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 530.05 m/z.pyridinyl}amino)carbonyl]amino}-3-[3,4,5-tris(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 15 Calculated (M − H)⁻ = 468.13m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 468.08 m/z.pyridinyl}amino)carbonyl]amino}-3-(3,5- dimethylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-[(3- 15 Calculated (M − H)⁻ =534.15 m/z; methyl-5-isoxazolyl)amino]-2-oxo-1,2-dihydro-3- Found (M −H)⁻ = 534.01 m/z. pyridinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 20Calculated (M − H)⁻ = 454.17 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M− H)⁻ = 454.04 m/z. pyridinyl}amino)carbonyl]amino}-3-(3-methylphenyl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 5Calculated (M − H)⁻ = 470.11 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M− H)⁻ = 470.03 m/z. pyridinyl}amino)carbonyl]amino}-3-[3-(methyloxy)phenyl]propanoic acid(3S)-3-[3,5-bis(methyloxy)phenyl]-3-{[({1-[(2- 3 Calculated (M − H)⁻ =500.12 m/z; chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M − H)⁻ =500.07 m/z. dihydro-3- pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 8 Calculated (M − H)⁻ = 504.13m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 504.06 m/z.quinolinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 20 Calculated (M − H)⁻ = 508.04m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 508.09 m/z.pyridinyl}amino)carbonyl]amino}-3-[3- (trifluoromethyl)phenyl]propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 2 Calculated (M − H)⁻ =595.21 m/z; [({ethyl[(ethylamino)carbonyl]amino}carbonyl) Found (M − H)⁻= 594.97 m/z. amino]-2-oxo-1,2-dihydro-3-pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-(1-azetanyl)-1-[(2- 5 Calculated (M − H)⁻ = 493.16 m/z;chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 493.05 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 30 Calculated (M − H)⁻ = 458.09m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 458.03 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- fluorophenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 40 Calculated (M − H)⁻ = 458.09m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 458.06 m/z.pyridinyl}amino)carbonyl]amino}-3-(3- fluorophenyl)propanoic acid(3S)-3-[({[1-[(2-chlorophenyl)methyl]-4-({2-[(2- 2 Calculated (M − H)⁻ =600.21 m/z; {[2-(methyloxy)ethyl]oxy}ethyl)oxy]ethyl}oxy)- Found (M −H)⁻ = 600.10 m/z. 2-oxo-1,2-dihydro-3-pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 25 Calculated (M − H)⁻ = 508.09m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 508.02 m/z.pyridinyl}amino)carbonyl]amino}-3-[4- (trifluoromethyl)phenyl]propanoicacid (3S)-3-{[({1-[(2-fluorophenyl)methyl]-4- 30 Calculated (M − H)⁻ =438.15 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 438.07 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-fluorophenyl)methyl]- 10 Calculated (M − H)⁻ =472.11 m/z; 4-hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 472.06 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 400 Calculated (M − H)⁻ =496.16 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 496.11 m/z.pyridinyl}amino)carbonyl]amino}-3-[4-(1,1-dimethylethyl)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-5-methyl- 70 Calculated (M − H)⁻ =452.14 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 451.99 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid3-(4-chlorophenyl)-3-{[({1-[(2- 30 Calculated (M − H)⁻ = 474.06 m/z;chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M − H)⁻ = 474.07 m/z.dihydro-3- pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)-4- 25 Calculated (M + H)⁺ =498.22 m/z; (2-pyridinyl)-1,6-dihydro-5- Found (M + H)⁺ = 498.10 m/z.pyrimidinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid3-(3-chlorophenyl)-3-{[({1-[(2- 30 Calculated (M − H)⁻ = 474.06 m/z;chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M − H)⁻ = 474.03 m/z.dihydro-3- pyridinyl}amino)carbonyl]amino}propanoic acid3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 40 Calculated (M − H)⁻ =508.02 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 507.97 m/z.pyridinyl}amino)carbonyl]amino}-3-(3,4- dichlorophenyl)propanoic acid

TABLE 4 Name IC₅₀ Mass Spectral Data(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1- 0.015 Calculated (M − H)⁻ =452.18 m/z; (phenylmethyl)-3- Found (M − H)⁻ = 452.10 m/z.azepanyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(3- 0.04 Calculated (M − H)⁻ =477.18 m/z; cyanophenyl)methyl]-2-oxo-3- Found (M − H)⁻ = 477.14 m/z.azepanyl}amino)carbonyl]amino}propanoic acid(3S)-3-(4-methylphenyl)-3-[({[2-oxo-1-(2- 0.6 Calculated (M − H)⁻ =410.11 m/z; thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 410.00m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[2-oxo-1- 0.5 Calculated (M − H)⁻ =434.13 m/z; (phenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 434.05 m/z.pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(4- 1 Calculated (M − H)⁻ =448.14 m/z; methylphenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =448.02 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-({[(1-{[4- 3 Calculated (M − H)⁻ =464.14 m/z; (methyloxy)phenyl]methyl}-2-oxo-1,2-dihydro- Found (M − H)⁻= 464.03 m/z. 3-pyridinyl)amino]carbonyl}amino)propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(3- 1.5 Calculated (M − H)⁻ =448.15 m/z; methylphenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =448.04 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-[3,5-bis(methyloxy)phenyl]-3-[({[2-oxo- 0.7 Calculated (M − H)⁻ =456.12 m/z; 1-(2-thiophenylmethyl)-1,2-dihydro-3- Found(M − H)⁻ = 456.00m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-[4-(methyloxy)phenyl]-3-[({[2-oxo-1-(2- 0.8 Calculated (M − H)⁻ =426.11 m/z; thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 426.00m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[2-oxo-1-(2-thiophenylmethyl)-1,2- 2.5 Calculated (M − H)⁻ =464.09 m/z; dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found (M − H)⁻= 463.99 m/z. [3-(trifluoromethyl)phenyl]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[3- 50 Calculated (M − H)⁻ = 419.12m/z; (phenyloxy)phenyl]amino}carbonyl)amino] Found (M − H)⁻ = 418.97m/z. propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({3-[(2- 5Calculated (M − H)⁻ = 438.11 m/z;thiophenylmethyl)amino]phenyl}amino)carbonyl] Found (M − H)⁻ = 438.00m/z. amino}propanoic acid (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(3- 0.8Calculated (M − H)⁻ = 468.09 m/z;chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 468.01 m/z.pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-({[(2-oxo-1- 0.8 Calculated (M − H)⁻ =502.12 m/z; {[3-(trifluoromethyl)phenyl]methyl}-1,2- Found (M − H)⁻ =502.03 m/z. dihydro-3- pyridinyl)amino]carbonyl}amino)propanoic acid(3S)-3-(4-fluorophenyl)-3-[({[2-oxo-1-(2- 1.6 Calculated (M − H)⁻ =414.09 m/z; thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 414.01m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(4- 3 Calculated (M − H)⁻ =468.09 m/z; chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =467.99 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-({[(1-{[2- 0.5 Calculated (M − H)⁻ =464.14 m/z; (methyloxy)phenyl]methyl}-2-oxo-1,2-dihydro- Found (M − H)⁻= 464.04 m/z. 3-pyridinyl)amino]carbonyl}amino)propanoic acid(3S)-3-[3-(methyloxy)phenyl]-3-[({[2-oxo-1-(2- 1.4 Calculated (M − H)⁻ =426.11 m/z; thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 426.02m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[2-oxo-1-(2-thiophenylmethyl)-1,2- 1 Calculated (M − H)⁻ =396.10 m/z; dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found (M − H)⁻= 396.01 m/z. phenylpropanoic acid(3S)-3-[({[2-oxo-1-(2-thiophenylmethyl)-1,2- 0.3 Calculated (M − H)⁻ =486.13 m/z; dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found (M − H)⁻= 485.98 m/z. [3,4,5-tris(methyloxy)phenyl]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(2- 0.3 Calculated (M − H)⁻ =468.08 m/z; chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =468.03 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(4- 2 Calculated (M − H)⁻ =452.12 m/z; fluorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =452.00 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid3-(1,3-benzodioxol-5-yl)-2,2-difluoro-3-[({[2- >100 Calculated (M − H)⁻= 476.07 m/z; oxo-1-(2-thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ =476.00 m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({2-oxo-1- 14 Calculated (M − H)⁻ =478.16 m/z; [3-(phenyloxy)propyl]-1,2-dihydro-3- Found (M − H)⁻ = 478.09m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(3,5- 5 Calculated (M − H)⁻ =502.05 m/z; dichlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =501.94 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[1- 6 Calculated (M − H)⁻ = 426.16m/z; (cyclopentylmethyl)-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 426.09m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-{[({2-oxo-1- 15 Calculated (M − H)⁻ =454.09 m/z; [2-(2-thiophenyl)ethyl]-1,2-dihydro-3- Found (M − H)⁻ =453.99 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M + H)⁺ =440.14 m/z; 1,2-dihydro-3- Found (M + H)⁺ = 440.09 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-(2,3-dihydro-1-benzofuran-5-yl)-3-[({[2- 0.14 Calculated (M − H)⁻= 438.11 m/z; oxo-1-(2-thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ =437.99 m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(3-fluorophenyl)-3-[({[2-oxo-1-(2- 3 Calculated (M − H)⁻ = 414.09m/z; thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 413.99 m/z.pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[2-oxo-1-(2-thiophenylmethyl)-1,2- 1.5 Calculated (M − H)⁻ =464.09 m/z; dihydro-3-pyridinyl]amino}carbonyl)amino]-3- Found (M − H)⁻= 463.99 m/z. [4-(trifluoromethyl)phenyl]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({[6-oxo-1- 0.5 Calculated (M − H)⁻ =434.13 m/z; (phenylmethyl)-1,6-dihydro-3- Found (M − H)⁻ = 434.02 m/z.pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-[4-fluoro-3-(trifluoromethyl)phenyl]-3- 0.35 Calculated (M − H)⁻= 482.08 m/z; [({[2-oxo-1-(2-thiophenylmethyl)-1,2-dihydro- Found (M −H)⁻ = 481.97 m/z. 3-pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-[4-(1,1-dimethylethyl)phenyl]-3-[({[2- 2 Calculated (M − H)⁻ =452.16 m/z; oxo-1-(2-thiophenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ =452.02 m/z. pyridinyl]amino}carbonyl)amino]propanoic acid(3S)-3-(1,3-benzodioxol-5-yl)-3-[({butyl[2,5- 70 Calculated (M − H)⁻ =494.19 m/z; dioxo-1-(phenylmethyl)tetrahydro-1H-pyrrol-3- Found (M − H)⁻= 494.12 m/z. yl]amino}carbonyl)amino]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.04 Calculated (M + H)⁺ =516.16 m/z; 1,2-dihydro-3- Found (M + H)⁺ = 516.02 m/z.pyridinyl}amino)carbonyl]amino}-3-[3,4,5-tris(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2,6-dichlorophenyl)methyl]-2- 0.2 Calculated (M + H)⁺ =474.10 m/z; oxo-1,2-dihydro-3- Found (M + H)⁺ = 474.04 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.2 Calculated (M + H)⁺ =512.10 m/z; 1,2-dihydro-3- Found (M + H)⁺ = 512.04 m/z.pyridinyl}amino)carbonyl]amino}-3-[4-fluoro-3-(trifluoromethyl)phenyl]propanoic acid(3S)-3-{[({1-[(2-fluorophenyl)methyl]-2-oxo- 0.1 Calculated (M − H)⁻ =422.15 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 422.01 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-(4-methylphenyl)-3-{[({1-[(2- 0.1 Calculated (M − H)⁻ = 418.18m/z; methylphenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 418.02m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(2-bromophenyl)methyl]-2-oxo- 0.05 Calculated (M + H)⁺ =484.09 m/z; 1,2-dihydro-3- Found (M + H)⁺ = 484.03 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2,4-dichlorophenyl)methyl]-2- 0.4 Calculated (M + H)⁺ =474.10 m/z; oxo-1,2-dihydro-3- Found (M + H)⁺ = 474.05 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.04 Calculated (M − H)⁻ =466.11 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 466.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid(3R)-3-(1,3-benzodioxol-5-yl)-3-{[({1-[(2- 2 Calculated (M − H)⁻ =468.09 m/z; chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =467.97 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(4-methylphenyl)-3-({[(2-oxo-1-{[2- 1 Calculated (M + H)⁺ =474.10 m/z; (trifluoromethyl)phenyl]methyl}-1,2-dihydro-3- Found (M +H)⁺ = 474.09 m/z. pyridinyl)amino]carbonyl}amino)propanoic acid(3S)-3-{[({1-[(2,5-dichlorophenyl)methyl]-2- 0.15 Calculated (M + H)⁺ =474.10 m/z; oxo-1,2-dihydro-3- Found (M + H)⁺ = 474.04 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(2R)-2-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 50 Calculated (M − H)⁻ =424.10 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 423.99 m/z.pyridinyl}amino)carbonyl]amino}-3- phenylpropanoic acid(2R)-2-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 80 Calculated (M − H)⁻ =410.08 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 409.95 m/z.pyridinyl}amino)carbonyl]amino}-2- phenylethanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M − H)⁻ =452.14 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 451.96 m/z.pyridinyl}amino)carbonyl]amino}-3-(3,5- dimethylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M − H)⁻ =424.10 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 424.07 m/z.pyridinyl}amino)carbonyl]amino}-3- phenylpropanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M − H)⁻ =454.11 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 454.01 m/z.pyridinyl}amino)carbonyl]amino}-3-[4- (methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.1 Calculated (M − H)⁻ =440.10 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 440.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- hydroxyphenyl)propanoic acid(3S)-3-({[(1-{[3-(methyloxy)phenyl]methyl}-2- 0.2 Calculated (M − H)⁻ =434.17 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 434.01 m/z.pyridinyl)amino]carbonyl}amino)-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-bromophenyl)methyl]-2-oxo- 0.08 Calculated (M − H)⁻ =558.09 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 557.87 m/z.pyridinyl}amino)carbonyl]amino}-3-[3,4,5-tris(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.09 Calculated (M + H)⁺ =454.15 m/z; 1,2-dihydro-3- Found (M + H)⁺ = 454.07 m/z.pyridinyl}amino)carbonyl]amino}-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-[({[5-chloro-2-hydroxy-3- 8 Calculated (M − H)⁻ = 437.12 m/z;(phenylmethyl)phenyl]amino}carbonyl)amino]- Found (M − H)⁻ = 437.06 m/z.3-(4-methylphenyl)propanoic acid (3S)-3-(4-methylphenyl)-3-[({[3- 10Calculated (M − H)⁻ = 387.17 m/z;(phenylmethyl)phenyl]amino}carbonyl)amino] Found (M − H)⁻ = 387.00 m/z.propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.04Calculated (M − H)⁻ = 468.13 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 468.01m/z. pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.07 Calculated (M − H)⁻ =454.11 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 454.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- hydroxy-3-methylphenyl)propanoicacid (3S)-3-{[({1-[(2,3-dichlorophenyl)methyl]-2- 0.35 Calculated (M −H)⁻ = 472.08 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 471.94 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-([1,1′-biphenyl]-2-ylmethyl)-2- 2.5 Calculated (M − H)⁻ =480.19 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 480.05 m/z.pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.2 Calculated (M − H)⁻ =438.12 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 438.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(3- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 3 Calculated (M − H)⁻ =438.12 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 437.99 m/z.pyridinyl}amino)carbonyl]amino}-3-(2- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 0.3 Calculated (M − H)⁻ =464.13 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 464.03 m/z.pyridinyl}amino)carbonyl]amino}-3-(2,3- dihydro-1H-inden-5-yl)propanoicacid (3S)-3-{[({1-{(2-cyanophenyl)methyl]-2-oxo- 0.1 Calculated (M + H)⁺= 431.18 m/z; 1,2-dihydro-3- Found (M + H)⁺ = 431.09 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[2,6-bis(methyloxy)phenyl]-3-{[({1-[(2- 6 Calculated (M − H)⁻ =484.14 m/z; chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ =483.96 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(3-hydroxyphenyl)methyl]-2-oxo- 0.2 Calculated (M + H)⁺ =420.18 m/z; 1,2-dihydro-3- Found (M + H)⁺ = 422.05 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)- 0.1 Calculated (M − H)⁻ =419.17 m/z; 1,6-dihydro-5- Found (M − H)⁻ = 419.03 m/z.pyrimidinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-oxo- 0.1 Calculated (M − H)⁻ =438.12 m/z; 1,4-dihydro-3- Found (M − H)⁻ = 438.10 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-(4-methylphenyl)-3-{[({1-[(2- 1 Calculated (M + H)⁺ = 451.17 m/z;nitrophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M + H)⁺ = 451.07 m/z.pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(4-methylphenyl)-3-{[({1-[(4- 1 Calculated (M + H)⁺ = 451.17 m/z;nitrophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M + H)⁺ = 451.09 m/z.pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo- 3 Calculated (M − H)⁻ =456.10 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 456.04 m/z.pyridinyl}amino)carbonyl]amino}-3-(2,6- dihydroxyphenyl)propanoic acid(3S)-3-{[({1-[(2,6-difluorophenyl)methyl]-2- 0.3 Calculated (M − H)⁻ =440.14 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 440.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2,4-difluorophenyl)methyl]-2- 1.3 Calculated (M − H)⁻ =440.14 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 439.96 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2,5-difluorophenyl)methyl]-2- 0.8 Calculated (M − H)⁻ =440.14 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 439.96 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2- 0.09 Calculated (M − H)⁻ =453.13 m/z; methyl-6-oxo-1,6-dihydro-5- Found (M − H)⁻ = 453.00 m/z.pyrimidinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chloro-6- 0.1 Calculated (M − H)⁻ = 456.11 m/z;fluorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 455.94 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-bromo-5- 0.5 Calculated (M − H)⁻ = 500.06 m/z;fluorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 499.91 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chloro-4- 0.35 Calculated (M − H)⁻ = 456.11 m/z;fluorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 455.93 m/z;pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-bromophenyl)methyl]-2-oxo- 0.2 Calculated (M − H)⁻ =512.08 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 511.96 m/z.pyridinyl}amino)carbonyl]amino}-3-[3-methyl-4-(methyloxy)phenyl]propanoic acid (3S)-3-{[({1-[(3,5-dimethyl-4- 3Calculated (M − H)⁻ = 423.17 m/z;isoxazolyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 423.02 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-(4-methylphenyl)-3-{[({2-oxo-1-[(2,4,6- 2.5 Calculated (M − H)⁻ =446.21 m/z; trimethylphenyl)methyl]-1,2-dihydro-3- Found (M − H)⁻ =446.08 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-(4-methylphenyl)-3-{[({1-[(2-methyl- 1 Calculated (M − H)⁻ =425.13 m/z; 1,3-thiazol-4-yl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻= 424.99 m/z. pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-({[(1-{[4-(1,1- 6 Calculated (M − H)⁻ = 460.22 m/z;dimethylethyl)phenyl]methyl}-2-oxo-1,2- Found (M − H)⁻ = 460.07 m/z.dihydro-3-pyridinyl)amino]carbonyl}amino)-3- (4-methylphenyl)propanoicacid (3S)-3-[({[1-(1,3-benzoxazol-2-ylmethyl)-2- >10 Calculated (M − H)⁻= 445.15 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 445.01 m/z.pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-({[(1-{2-[(2-hydroxyphenyl)amino]-2- >10 Calculated (M − H)⁻ =463.16 m/z; oxoethyl}-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 463.06 m/z.pyridinyl)amino]carbonyl}amino)-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-nitrophenyl)methyl]- 4 Calculated (M − H)⁻ =483.11 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 483.01 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(5-chloro-2- 2.5 Calculated (M − H)⁻ = 456.11 m/z;fluorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 456.00 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-amino-6- 2 Calculated (M − H)⁻ = 453.13 m/z;chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 453.02 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-({[(1-{[2-fluoro-4- 3 Calculated (M − H)⁻ = 490.14 m/z;(trifluoromethyl)phenyl]methyl}-2-oxo-1,2- Found (M − H)⁻ = 489.99 m/z.dihydro-3-pyridinyl)amino]carbonyl}amino)-3- (4-methylphenyl)propanoicacid (3S)-3-{[({1-[(5-chloro-2-thiophenyl)methyl]-2- 1.3 Calculated (M −H)⁻ = 444.08 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 443.97 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-bromo-5-nitrophenyl)methyl]- 2 Calculated (M − H)⁻ =527.06 m/z; 2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 526.95 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid3-(4-chlorophenyl)-3-{[({1-[(2- 0.03 Calculated (M − H)⁻ = 474.06 m/z;chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M − H)⁻ = 474.07 m/z.dihydro-3- pyridinyl}amino)carbonyl]amino}propanoic acid(3S)-3-[({[2-methyl-6-oxo-1-(phenylmethyl)-4- 0.025 Calculated (M + H)⁺= 498.22 m/z; (2-pyridinyl)-1,6-dihydro-5- Found (M + H)⁺ = 498.10 m/z.pyrimidinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(5-amino-2- 0.08 Calculated (M − H)⁻ = 497.08 m/z;bromophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 497.02 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2,5-dimethylphenyl)methyl]-2- 0.15 Calculated (M − H)⁻ =432.19 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 432.04 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid3-(3-chlorophenyl)-3-{[({1-[(2- 0.03 Calculated (M − H)⁻ = 474.06 m/z;chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2- Found (M − H)⁻ = 474.03 m/z.dihydro-3-pyridinyl}amino) carbonyl]amino}propanoic acid3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 0.04 Calculated (M − H)⁻ =508.02 m/z; oxo-1,2-dihydro-3- Found (M − H)⁻ = 507.97 m/z.pyridinyl}amino)carbonyl]amino}-3-(3,4- dichlorophenyl)propanoic acid(3S)-3-({[(1-{[5-(acetylamino)-2- 0.2 Calculated (M − H)⁻ = 539.09 m/z;bromophenyl]methyl}-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 539.02 m/z.pyridinyl)amino]carbonyl}amino)-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-({2-bromo-5- 0.25 Calculated (M − H)⁻ = 575.06 m/z;[(methylsulfonyl)amino]phenyl}methyl)-2-oxo- Found (M − H)⁻ = 575.01m/z. 1,2-dihydro-3- pyridinyl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid 3-(4-chlorophenyl)-3-{[({1-[(2- 0.4Calculated (M − H)⁻ = 458.07 m/z;chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 457.96 m/z.pyridinyl}amino)carbonyl]amino}propanoic acid3-(3-chlorophenyl)-3-{[({1-[(2- 1 Calculated (M − H)⁻ = 458.07 m/z;chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 457.93 m/z.pyridinyl}amino)carbonyl]amino}propanoic acid3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-1,2- 1 Calculated (M − H)⁻ =492.03 m/z; dihydro-3-pyridinyl}amino)carbonyl]amino}-3- Found (M − H)⁻= 491.85 m/z. (3,4-dichlorophenyl)propanoic acid(3S)-3-{[({1-[(2-bromo-4- 1 Calculated (M − H)⁻ = 516.03 m/z;chlorophenyl)methyl]-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 515.91 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(4-chlorophenyl)methyl]-2-oxo- 2 Calculated (M − H)⁻ =438.12 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 437.88 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 0.035 Calculated (M − H)⁻ =498.14 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 498.05 m/z.pyridinyl}amino)carbonyl]amino}-3-[2,3-dimethyl-4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 0.015 Calculated (M − H)⁻ =524.08 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 524.03 m/z.pyridinyl}amino)carbonyl]amino}-3-{4-[(trifluoromethyl)oxy]phenyl}propanoic acid(3R)-3-[({[1-[(2-chlorophenyl)methyl]-4-(1,4- 0.1 Calculated (M − H)⁻ =489.19 m/z; oxazinan-4-yl)-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 489.13m/z. pyridinyl]amino}carbonyl)amino]-5- methylhexanoic acid(3S)-3-[({[4-hydroxy-6-methyl-2-oxo-1- 0.035 Calculated (M − H)⁻ =434.17 m/z; (phenylmethyl)-1,2-dihydro-3- Found (M − H)⁻ = 434.08 m/z.pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-2-oxo-4- 0.030 Calculated (M − H)⁻= 559.14 m/z; [(propylsulfonyl)amino]-1,2-dihydro-3- Found (M − H)⁻ =559.04 m/z. pyridinyl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 0.025 Calculated (M − H)⁻= 468.13 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 468.06 m/z.pyridinyl}amino)carbonyl]amino}-3-(4- ethylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4- 0.02 Calculated (M − H)⁻ =484.13 m/z; hydroxy-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 484.06 m/z.pyridinyl}amino)carbonyl]amino}-3-[4- (ethyloxy)phenyl]propanoic acid(3S)-3-[({[4-hydroxy-2-oxo-1-(phenylmethyl)- 0.030 Calculated (M − H)⁻ =420.16 m/z; 1,2-dihydro-3- Found (M − H)⁻ = 420.08 m/z.pyridinyl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid

TABLE 5 Name IC₅₀ (μM) Mass Spectral Data(3S)-3-[({[1-(3-tert-butyl-2-methoxybenzyl)-2-oxo- 2.5 Calculated (M −H)⁻ = 490.23 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 490.11 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(4-fluorobenzyl)-2-oxo-1,2- 2 Calculated (M − H)⁻ = 422.12m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found (M − H)⁻ =422.00 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.025 Calculated (M − H)⁻= 526.08 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 526.01 m/z. [4-fluoro-3-(trifluoromethyl)phenyl]propanoic acid(3S)-3-[({[1-(2,5-dimethylbenzyl)-4-hydroxy-2- 0.02 Calculated (M − H)⁻= 448.19 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 448.00 m/z.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[4-hydroxy-1-(2-methylbenzyl)-2-oxo- 0.02 Calculated (M − H)⁻= 434.17 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 434.05 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-hydroxybenzyl)-2-oxo-1,2- 0.2 Calculated (M − H)⁻ =420.16 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found (M −H)⁻ = 420.09 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(3-chlorobenzyl)-2-oxo-1,2- 0.5 Calculated (M − H)⁻ =438.12 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found (M −H)⁻ = 438.01 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-2-oxo- 0.1 Calculated (M − H)⁻ =468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M −H)⁻ = 468.08 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.035 Calculated (M − H)⁻= 498.14 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 497.94 m/z. (4-methoxy-3,5-dimethylphenyl)propanoic acid4-{[3-[({[(1S)-2-carboxy-1-(4- 0.004 Calculated (M − H)⁻ = 573.15 m/z;methylphenyl)ethyl]amino}carbonyl)amino]-1-(2- Found (M − H)⁻ = 572.92m/z. chlorobenzyl)-2-oxo-1,2-dihydropyridin-4- yl]amino}benzoic acid(3S)-3-{[({1-(2-chlorobenzyl)-4-[(2,2- 0.01 Calculated (M − H)⁻ = 537.19m/z; dimethylpropanoyl)amino]-2-oxo-1,2- Found (M − H)⁻ = 536.88 m/z.dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoicacid (3S)-3-[({[1-(2-chloro-5-methoxybenzyl)-2-oxo- 0.09 Calculated (M −H)⁻ = 468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 467.99 m/z. (4-methylphenyl)propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.19 Calculated (M − H)⁻= 378.09 m/z; 1,2-dihydropyridin-3- Found (M − H)⁻ = 378.01 m/z.yl]amino}carbonyl)amino]butanoic acid(3S)-3-[({[4-{[(tert-butylamino)carbonyl]amino}-1- 0.01 Calculated (M −H)⁻ = 552.20 m/z; (2-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3- Found (M− H)⁻ = 551.89 m/z. yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-hydroxybenzyl)-2-oxo- 0.25 Calculated (M − H)⁻= 454.12 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 454.03 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-cyanobenzyl)-4-hydroxy-2-oxo-1,2- 0.009 Calculated (M −H)⁻ = 445.15 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found(M − H)⁻ = 445.01 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(2,4-dichlorobenzyl)-4-hydroxy-2-oxo- 0.06 Calculated (M −H)⁻ = 488.08 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 487.96 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[4-hydroxy-1-(2-methoxybenzyl)-2-oxo- 0.08 Calculated (M − H)⁻= 450.17 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 450.02 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.08 Calculated (M − H)⁻= 498.14 m/z; 1,2-dihydropyridin-3-yl[amino}carbonyl)amino]-3- Found (M− H)⁻ = 497.95 m/z. (4-methoxy-2,5-dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-hydroxybenzyl)-2-oxo- 0.1 Calculated (M − H)⁻ =454.12 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M −H)⁻ = 454.05 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(3-tert-butyl-2-hydroxybenzyl)-2-oxo- 4 Calculated (M − H)⁻= 476.02 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 476.00 m/z. (4-methylphenyl)propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.3 Calculated (M − H)⁻ =454.17 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M −H)⁻ = 454.05 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M − H)⁻= 468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 467.95 m/z. (3-ethylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.01 Calculated (M − H)⁻= 498.10 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 497.85 m/z. (2,3-dihydro-1,4-benzodioxin-6-yl)propanoic acid(3S)-3-[({[1-(2,5-difluorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M −H)⁻ = 456.14 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 455.96 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 30 Calculated (M − H)⁻ =468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- Found (M −H)⁻ = 467.87 m/z. (4-methylphenyl)butanoic acid(3S)-3-{[({1-[2-chloro-5-(methylthio)benzyl]-4- 0.015 Calculated (M −H)⁻ = 500.10 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =499.92 m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.005 Calculated (M − H)⁻= 514.10 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 513.86 m/z. (7-methoxy-1,3-benzodioxol-5-yl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.002 Calculated (M − H)⁻= 514.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 513.90 m/z. (3-ethoxy-4-methoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M − H)⁻= 488.10 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 487.92 m/z. (3-fluoro-4-methoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.002 Calculated (M − H)⁻= 500.12 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 500.01 m/z. (3,4-dimethoxyphenyl)propanoic acid(3S)-3-[({[1-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2- 0.022 Calculated (M −H)⁻ = 438.18 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found(M − H)⁻ = 438.00 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(2-methoxybenzyl)-2-oxo-1,2- 0.25 Calculated (M − H)⁻ =434.17 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found (M −H)⁻ = 433.95 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.05 Calculated (M − H)⁻= 468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 467.94 m/z. (2,5-dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-methoxybenzyl)-4- 0.012 Calculated (M − H)⁻ =484.13 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 484.03m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[3,5-bis(trifluoromethyl)benzyl]-4- 0.3 Calculated (M − H)⁻= 556.13 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =555.95 m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(4-tert-butylbenzyl)-4-hydroxy-2-oxo- 0.03 Calculated (M −H)⁻ = 476.22 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 476.05 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(3-chlorobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M − H)⁻= 454.12 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 453.99 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2-oxo- 0.007 Calculated (M − H)⁻= 454.12 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 454.00 m/z. (4-methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-2-oxo-1-[3- 0.017 Calculated (M − H)⁻ = 488.14 m/z;(trifluoromethyl)benzyl]-1,2-dihydropyridin-3- Found (M − H)⁻ = 487.99m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-bromobenzyl)-4-hydroxy-2-oxo- 0.015 Calculated (M − H)⁻= 498.07 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 497.97 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(3,4-dichlorobenzyl)-4-hydroxy-2-oxo- 0.045 Calculated (M −H)⁻ = 488.08 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 487.96 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[4-hydroxy-1-(4-methylbenzyl)-2-oxo- 0.025 Calculated (M − H)⁻= 434.17 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 434.05 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 0.003 Calculated (M − H)⁻ =484.13 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 484.02m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-2-oxo-1-[4- 0.02 Calculated (M − H)⁻ = 488.14 m/z;(trifluoromethyl)benzyl]-1,2-dihydropyridin-3- Found (M − H)⁻ = 487.99m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.02 Calculated (M − H)⁻= 524.08 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 523.91 m/z. [3-(trifluoromethoxy)phenyl]propanoic acid(3S)-3-[({[4-hydroxy-1-(3-methylbenzyl)-2-oxo- 0.055 Calculated (M − H)⁻= 434.17 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 433.99 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[4-hydroxy-2-oxo-1-(pyridin-2-ylmethyl)- 0.045 Calculated (M −H)⁻ = 421.15 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 421.06 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.005 Calculated (M −H)⁻ = 468.13 m/z; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 467.99m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2,4-difluorobenzyl)-4-hydroxy-2-oxo- 0.03 Calculated (M −H)⁻ = 456.14 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 456.01 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2,6-difluorobenzyl)-4-hydroxy-2-oxo- 0.008 Calculated (M −H)⁻ = 456.14 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 456.01 m/z. (4-methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-2-oxo-1-[3- 0.045 Calculated (M − H)⁻ = 504.14 m/z;(trifluoromethoxy)benzyl]-1,2-dihydropyridin-3- Found (M − H)⁻ = 503.98m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-2-oxo-1-[4- 0.025 Calculated (M − H)⁻ = 504.14 m/z;(trifluoromethoxy)benzyl]-1,2-dihydropyridin-3- Found (M − H)⁻ = 503.98m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 0.0015 Calculated (M − H)⁻ =530.13 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 529.91m/z. yl]amino}carbonyl)amino]-3-(3,5- dimethoxyphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 0.05 Calculated (M − H)⁻ =430.08 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2- Found (M −H)⁻ = 429.94 m/z. furyl)propanoic acid (3S)-3-{[({4-hydroxy-2-oxo-1-[2-0.02 Calculated (M − H)⁻ = 488.14 m/z;(trifluoromethyl)benzyl]-1,2-dihydropyridin-3- Found (M − H)⁻ = 487.96m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.15 Calculated (M − H)⁻= 468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- Found (M− H)⁻ = 467.99 m/z. (4-methylphenyl)butanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.0008 Calculated (M −H)⁻ = 528.15 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 527.96 m/z. (3,4-diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M − H)⁻= 484.12 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 483.94 m/z. (3-ethoxyphenyl)propanoic acid(3S)-3-[({[4-hydroxy-1-(3-methoxybenzyl)-2-oxo- 0.04 Calculated (M − H)⁻= 450.17 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 450.00 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2,3-dichlorobenzyl)-4-hydroxy-2-oxo- 0.13 Calculated (M −H)⁻ = 488.08 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 487.92 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-benzyl-2-oxo-5-(trifluoromethyl)-1,2- 1.5 Calculated (M −H)⁻ = 472.15 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found(M − H)⁻ = 471.89 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(3,5-dimethylbenzyl)-4-hydroxy-2- 0.06 Calculated (M − H)⁻= 448.19 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 448.02 m/z.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 0.04 Calculated (M − H)⁻ =554.09 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 553.98m/z. yl]amino}carbonyl)amino]-3-[4- (trifluoromethoxy)phenyl]propanoicacid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M− H)⁻ = 484.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-Found (M − H)⁻ = 483.95 m/z. (3-methoxy-4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M − H)⁻= 514.14 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 513.95 m/z. (3,5-dimethoxy-4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.04 Calculated (M −H)⁻ = 524.20 m/z; pentyl-1,2-dihydropyridin-3- Found (M − H)⁻ = 523.98m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.005 Calculated (M + H)= 468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M + H)⁺ = 467.99 m/z. (3,4-dimethylphenyl)propanoic acid(3S)-3-[({[1-(2,4-dichlorobenzyl)-4-hydroxy-5- 0.02 Calculated (M − H)⁻= 502.09 m/z; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 501.89m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid[2-({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- >10 Calculated (M − H)⁻ =455.11 m/z; dihydropyridin-3-yl]amino}carbonyl)-1-(4- Found (M − H)⁻ =454.97 m/z. methylphenyl)hydrazino]acetic acid(3S)-3-[({[1-(2-chlorobenzyl)-5-ethyl-4-hydroxy-2- 0.01 Calculated (M −H)⁻ = 482.15 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 482.00 m/z.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 0.05 Calculated (M − H)⁻ =441.09 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M − H)⁻= 441.00 m/z. pyridin-3-ylpropanoic acid(3S)-3-[({[5-butyl-1-(2-chlorobenzyl)-4-hydroxy-2- 0.025 Calculated (M −H)⁻ = 510.18 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 509.98 m/z.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl]- 0.01 Calculated (M −H)⁻ = 522.10 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =521.97 m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 0.005 Calculated (M − H)⁻ =484.13 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 484.00m/z. yl]amino}carbonyl)amino]-3-(3- methylphenyl)propanoic acid(3S)-3-[({[1-(2,6-dichlorobenzyl)-4-hydroxy-2-oxo- 0.013 Calculated (M −H)⁻ = 488.08 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 487.91 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-fluorobenzyl)-4-hydroxy- 0.014 Calculated (M −H)⁻ = 472.11 m/z; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 471.96m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.01 Calculated (M −H)⁻ = 482.15 m/z; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =481.98 m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-5-methyl- 0.02 Calculated (M −H)⁻ = 468.13 m/z; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 467.94m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M + H)⁺= 496.16 m/z; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M +H)⁺ = 495.99 m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoicacid (3S)-3-{[({4-hydroxy-5-methyl-1-[4- 0.02 Calculated (M − H)⁻ =512.15 m/z; (methylsulfonyl)benzyl]-2-oxo-1,2-dihydropyridin- Found (M −H)⁻ = 511.96 m/z. 3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid(3S)-3-[({[4-hydroxy-1-(4-methoxybenzyl)-2-oxo- 0.02 Calculated (M − H)⁻= 450.17 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 449.99 m/z. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.02 Calculated (M −H)⁻ = 496.16 m/z; propyl-1,2-dihydropyridin-3- Found (M − H)⁻ = 495.94m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-({[(1-{4-[(dimethylamino)sulfonyl]benzyl}- 0.035 Calculated (M −H)⁻ = 527.16 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =526.96 m/z. yl)amino]carbonyl}amino)-3-(4- methylphenyl)propanoic acid(3S)-3-[({[4-hydroxy-1-(mesitylmethyl)-2-oxo-1,2- 0.06 Calculated (M −H)⁻ = 462.20 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found(M − H)⁻ = 462.02 m/z. methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.02 Calculated (M − H)⁻= 508.16 m/z; 1,2,5,6,7,8-hexahydroquinolin-3- Found (M − H)⁻ = 507.96m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-5-ethyl-4-hydroxy-6- 0.025 Calculated (M −H)⁻ = 496.16 m/z; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =495.96 m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.4 Calculated (M − H)⁻ =468.13 m/z; 1,2-dihydropyridin-3- Found (M − H)⁻ = 467.85 m/z.yl]amino}carbonyl)(methyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-1-[2-(methylthio)benzyl]-2- 0.02 Calculated (M −H)⁻ = 466.14 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 465.97 m/z.yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-({[(1-{2-[(dimethylamino)sulfonyl]benzyl}- 0.03 Calculated (M −H)⁻ = 527.16 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =526.97 m/z. yl)amino]carbonyl}amino)-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2,6-dimethoxybenzyl)-4-hydroxy-2- 0.01 Calculated (M − H)⁻= 480.18 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 480.00 m/z.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-2-oxo-1-[2- 0.025 Calculated (M − H)⁻ = 504.14 m/z;(trifluoromethoxy)benzyl]-1,2-dihydropyridin-3- Found (M − H)⁻ = 503.96m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.35 Calculated (M − H)⁻= 522.10 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- Found (M− H)⁻ = 521.95 m/z. [3-(trifluoromethyl)phenyl]butanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M − H)⁻= 498.14 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 497.97 m/z. (3-propoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.003 Calculated (M +H)⁺ = 528.19 m/z; propyl-1,2-dihydropyridin-3- Found (M + H)⁺ = 528.02m/z. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6- 0.006 Calculated (M − H)⁻ =482.15 m/z; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 481.95m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.005 Calculated (M −H)⁻ = 570.20 m/z; propyl-1,2-dihydropyridin-3- Found (M − H)⁻ = 569.98m/z. yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-(3-butoxyphenyl)-3-[({[1-(2-chlorobenzyl)- 0.005 Calculated (M +H)⁺ = 514.17 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =514.00 m/z. yl]amino}carbonyl)amino]propanoic acid(3S)-3-{[({1-[2-chloro-5-(methylsulfonyl)benzyl]- 0.003 Calculated (M −H)⁻ = 532.10 m/z; 4-hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =531.94 m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.08 Calculated (M − H)⁻= 468.13 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- Found (M− H)⁻ = 468.03 m/z. (2-methylphenyl)butanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M − H)⁻= 514.14 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 513.95 m/z. [3-(2-methoxyethoxy)phenyl]propanoic acid(3S)-3-[({[1-(4-chloro-2-methoxybenzyl)-4- 0.025 Calculated (M − H)⁻ =484.13 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 483.93m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.003 Calculated (M − H)⁻= 556.18 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 555.94 m/z. (3,4-dipropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.12 Calculated (M − H)⁻= 522.18 m/z; 2,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-3- Found (M− H)⁻ = 521.98 m/z. yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 12 Calculated (M − H)⁻ =530.15 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found (M −H)⁻ = 529.92 m/z. 4,4-diphenylbutanoic acid(3S)-3-{[({1-[2-(difluoromethoxy)benzyl]-4- 0.075 Calculated (M − H)⁻ =486.15 m/z; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 486.00m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-5-methyl-2-oxo-1-[(1R)-1- 4 Calculated (M − H)⁻ =448.19 m/z; phenylethyl]-1,2-dihydropyridin-3- Found (M − H)⁻ = 447.99m/z. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.03 Calculated (M −H)⁻ = 496.16 m/z; propyl-1,2-dihydropyridin-3- Found (M − H)⁻ = 495.96m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.05 Calculated (M − H)⁻= 496.16 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 495.98 m/z. (3,4-diethylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.05 Calculated (M − H)⁻= 476.08 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 475.93 m/z. (3,5-difluorophenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 0.02 Calculated (M − H)⁻ =490.12 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2- Found (M −H)⁻ = 489.97 m/z. naphthyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 0.025 Calculated (M + H)⁺= 446.11 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(5- Found (M +H)⁺ = 446.08 m/z. methyl-2-furyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.025 Calculated (M − H)⁻= 584.21 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 583.98 m/z. (3,4-dibutoxyphenyl)propanoic acid(3S)-3-{[({4-hydroxy-1-[2- 0.035 Calculated (M + H)⁺ = 500.15 m/z;(methylsulfonyl)benzyl]-2-oxo-1,2-dihydropyridin- Found (M + H)⁺ =500.01 m/z. 3-yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 0.2 Calculated (M − H)⁻ =490.12 m/z; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(1- Found (M −H)⁻ = 489.91 m/z. naphthyl)propanoic acid(3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.03 Calculated (M −H)⁻ = 526.17 m/z; propyl-1,2-dihydropyridin-3- Found (M − H)⁻ = 525.95m/z. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2-oxo-5- 0.015 Calculated (M −H)⁻ = 570.20 m/z; propyl-1,2-dihydropyridin-3- Found (M − H)⁻ = 569.97m/z. yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2,6-dimethylbenzyl)-4-hydroxy-2- 0.035 Calculated (M − H)⁻= 448.19 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 448.02 m/z.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[3,5-bis(trifluoromethyl)phenyl]-3-[({[1-(2- 0.22 Calculated (M −H)⁻ = 576.08 m/z; chlorobenzyl)-4-hydroxy-2-oxo-1,2-dihydropyridin-Found (M − H)⁻ = 575.91 m/z. 3-yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.006 Calculated (M − H)⁻= 506.09 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M− H)⁻ = 505.93 m/z. [3-(difluoromethoxy)phenyl]propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 0.225 Calculated (M − H)⁻= 455.11 m/z; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-4- Found (M− H)⁻ = 455.09 m/z. pyridin-2-ylbutanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.0006 Calculated (M −H)⁻ = 542.17 m/z; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 542.06m/z. yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.002 Calculated (M −H)⁻ = 499.15 m/z; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 498.07m/z. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 0.020 Calculated (M +H)⁺ = 500.16 m/z; 2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 500.02m/z. yl]amino}carbonyl)amino]-3-(3-methoxy-4- methylphenyl)propanoicacid 3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 0.030 Calculated (M− H)⁻ = 504.13 m/z; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 504.04m/z. yl]amino}carbonyl)amino]-3-(2-naphthyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.015 Calculated (M −H)⁻ = 526.17 m/z; 5,6-dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M −H)⁻ = 525.95 m/z. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoicacid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.025 Calculated(M − H)⁻ = 526.17 m/z; 5,6-dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M− H)⁻ = 525.97 m/z. yl]amino}carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.004 Calculated (M −H)⁻ = 570.20 m/z; 5,6-dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M −H)⁻ = 570.00 m/z. yl]amino}carbonyl)amino]-3-(3,4-diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-cyanobenzyl)-4-hydroxy- 0.007 Calculated (M −H)⁻ = 479.11 m/z; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 478.90m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 0.03 Calculated (M −H)⁻ = 496.16 m/z; 5,6-dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M −H)⁻ = 495.97 m/z. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoicacid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6- 0.015 Calculated (M −H)⁻ = 512.16 m/z; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =511.95 m/z. yl]amino}carbonyl)amino]-3-(3-methoxy-4-methylphenyl)propanoic acid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6-0.003 Calculated (M − H)⁻ = 556.18 m/z;dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 555.99 m/z.yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid

TABLE 6 Mass Spectral Data Compound IC₅₀ (nM) ( m/z)(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 2500 Calculated (M −H)⁻ = 504.13; dihydropyridin-3-yl]amino}carbonyl)amino]-4-(1- Found (M −H)⁻ = 503.97. naphthyl)butanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6- 30 Calculated (M − H)⁻ =512.16; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 511.99.yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5,6- 40 Calculated (M − H)⁻ =496.16; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 496.05.yl]amino}carbonyl)amino]-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 5 Calculated (M − H)⁻ =498.15; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =497.91. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 2 Calculated (M − H)⁻ =572.18. hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =571.96. yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 6 Calculated (M − H)⁻ =528.15; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =527.95. yl]amino}carbonyl)amino]-3-(3-methoxy-4- methylphenyl)propanoicacid (3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 3 Calculated (M − H)⁻ =528.15; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =527.99. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 15 Calculated (M −H)⁻ = 556.09; dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3- Found (M −H)⁻ = 555.97. (1,1,2,2-tetrafluoroethoxy)phenyl]propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 700 Calculated (M −H)⁻ = 488.08; dihydropyridin-3-yl]amino}carbonyl)amino]-4-(2- Found (M −H)⁻ = 487.96. chlorophenyl)butanoic acid(3S)-3-{[({4-hydroxy-1-[3-(methylthio)benzyl]-2- 20 Calculated (M − H)⁻= 466.14; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 466.04.yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 15 Calculated (M − H)⁻= 482.15; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 482.02.yl]amino}carbonyl)amino]-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 3 Calculated (M − H)⁻ =512.16. hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =512.03. yl]amino}carbonyl)amino]-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-5-cyclopropyl-4- 20 Calculated (M + H)⁺ =496.16; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 496.05.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(4-chlorobenzyl)-4-hydroxy-2-oxo- 50 Calculated (M − H)⁻ =494.15; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =494.02. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(3-chlorobenzyl)-4-hydroxy-5-methyl- 20 Calculated (M − H)⁻= 468.13; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 468.02.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2,6-dichlorobenzyl)-4-hydroxy-5- 20 Calculated (M − H)⁻ =502.09; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 501.92.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[4-hydroxy-5-methyl-1-(4-methylbenzyl)- 150 Calculated (M −H)⁻ = 448.19; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 448.05.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid3-(1-benzofuran-2-yl)-3-[({[1-(2-chlorobenzyl)-4- 140 Calculated (M −H)⁻ = 480.10; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M-−H)⁻ =479.96. yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 3 Calculated (M − H)⁻ =524.16; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =523.95. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 15 Calculated (M − H)⁻ =520.13; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6- Found (M − H)⁻ =520.00. methoxy-2-naphthyl)propanoic acid(3S)-3-[({[1-(3,5-dimethoxybenzyl)-4-hydroxy-5- 70 Calculated (M − H)⁻ =494.19; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 494.04.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2,6-difluorobenzyl)-4-hydroxy-5- 25 Calculated (M − H)⁻ =470.15; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 470.03.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 3 Calculated (M + H)⁺ =570.20; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =570.00. yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-{[({4-hydroxy-1-[3-(methylsulfonyl)benzyl]- 25 Calculated (M −H)⁻ = 498.13; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 498.01.yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 3 Calculated (M − H)⁻= 556.19; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 556.02.yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 4 Calculated (M − H)⁻= 512.16; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 512.02.yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 45 Calculated (M − H)⁻= 496.16; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 496.01.yl]amino}carbonyl)amino]-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 25 Calculated (M − H)⁻= 512.16; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 511.97.yl]amino}carbonyl)amino]-3-(3-methoxy-4- methylphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 115 Calculated (M − H)⁻ =458.11; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4,5- Found (M − H)⁻= 457.99. dimethyl-2-furyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 160 Calculated (M − H)⁻ =520.13; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4- Found (M − H)⁻ =519.97. methoxy-1-naphthyl)propanoic acid(3R)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 115 Calculated (M −H)⁻ = 468.13; dihydropyridin-3-yl]amino}carbonyl)amino]-5- Found (M −H)⁻ = 467.98. phenylpentanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 12 Calculated (M −H)⁻ = 534.14; dihydroquinolin-3-yl]amino}carbonyl)amino]-3-(3- Found (M− H)⁻ = 533.94. ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 18 Calculated (M + H)⁺ =510.18; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =510.06. yl]amino}carbonyl)amino]-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 7 Calculated (M + H)⁺= 500.16; 2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 500.06.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 3 Calculated (M − H)⁻= 512.16; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 512.03.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-5-cyclopropyl-4- 14 Calculated (M + H)⁺ =526.17; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 526.01.yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-5-cyclopropyl-4- 6 Calculated (M + H)⁺ =570.20; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 570.04.yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 30 Calculated (M −H)⁻ = 506.09; dihydropyridin-3-yl]amino}carbonyl)amino]-3-[4- Found (M −H)⁻ = 505.96. (difluoromethoxy)phenyl]propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 105 Calculated (M − H)⁻ =491.11; dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M − H)⁻ =490.96. quinolin-2-ylpropanoic acid(3S)-3-[({[1-(2-fluoro-6-methoxybenzyl)-4-hydroxy- 10 Calculated (M −H)⁻ = 482.17; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =482.02. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 15 Calculated (M + H)⁺ =528.19; hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3- Found (M + H)⁺ =528.04. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 7 Calculated (M + H)⁺ =558.20; hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3- Found (M + H)⁺ =558.07. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(5-chloro-2-fluorobenzyl)-4-hydroxy-5- 15 Calculated (M −H)⁻ = 486.12; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =486.00. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 14 Calculated (M −H)⁻ = 534.14; dihydroquinolin-3-yl]amino}carbonyl)amino]-3-(3- Found (M− H)⁻ = 533.95. methoxy-4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 4 Calculated (M − H)⁻= 578.17; dihydroquinolin-3-yl]amino}carbonyl)amino]-3- Found (M − H)⁻ =577.99. (3,4-diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 25 Calculated (M −H)⁻ = 518.15; dihydroquinolin-3-yl]amino}carbonyl)amino]-3- Found (M −H)⁻ = 517.96. (3,4-dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 150 Calculated (M +H)⁺ = 443.11; dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M +H)⁺ = 443.03. pyridin-2-ylpropanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 3 Calculated (M − H)⁻= 498.14; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3- Found (M − H)⁻= 498.04. isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 7 Calculated (M − H)⁻= 528.15; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3,5- Found (M −H)⁻ = 528.02. diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5- 60 Calculated (M + H)⁺ =498.18; isopropyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 498.05.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(5-fluoro-2-methylbenzyl)-4-hydroxy- 20 Calculated (M + H)⁺= 468.19; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 468.07.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-{[({4-hydroxy-5-methyl-2-oxo-1-[(1S)-1- 1500 Calculated (M + H)⁺= 450.20; phenylethyl]-1,2-dihydropyridin-3- Found (M + H)⁺ = 450.07.yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 3 Calculated (M + H)⁺ =602.23; hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3- Found (M + H)⁺ =602.04. yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-isopropoxybenzyl)-4- 7 Calculated (M − H)⁻ =526.17; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =526.04. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 15 Calculated (M + H)⁺ =558.20; hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3- Found (M + H)⁺ =588.05. yl]amino}carbonyl)amino]-3-(3-methoxy-4- methylphenyl)propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 2 Calculated (M +H)⁺ = 544.19; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =544.04. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(5-acetyl-2-methoxybenzyl)-4-hydroxy- 33 Calculated (M −H)⁻ = 492.18; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 492.04.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5- 35 Calculated (M − H)⁻ =548.16; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 548.01.yl]amino}carbonyl)amino]-3-(6-methoxy-2- naphthyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methoxybenzyl)-4- 17 Calculated (M + H)⁺ =542.21; hydroxy-2-oxo-5-propyl-1,2-dihydropyridin-3- Found (M + H)⁺ =542.05. yl]amino}carbonyl)amino]-3-(3,4- dimethylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 3 Calculated (M − H)⁻= 493.13; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(1- Found (M − H)⁻= 492.95. methyl-1H-indol-5-yl)propanoic acid(3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 18 Calculated (M + H)⁺= 471.14; 3-oxo-2,3-dibydropyridazin-4- Found (M + H)⁺ = 471.00.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 5 Calculated (M − H)⁻= 534.14; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 533.91.yl]amino}carbonyl)amino]-3-(6-methoxy-2- naphthyl)propanoic acid(3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 5 Calculated (M + H)⁺= 501.15; 3-oxo-2,3-dihydropyridazin-4- Found (M + H)⁺ = 501.01.yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 30 Calculated (M + H)⁺ =448.07; dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found (M + H)⁺ =447.97. thien-2-ylpropanoic acid(3S)-3-[({[5-chloro-1-(2-chlorobenzyl)-4-hydroxy-2- 6 Calculated (M −H)⁻ = 488.08; oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 487.97.yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-(3-butoxyphenyl)-3-[({[1-(2-chlorobenzyl)-4- 20 Calculated (M −H)⁻ = 552.19; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ =552.01. cyclopenta[b]pyridin-3- yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 5 Calculated (M − H)⁻= 524.16; dihydropyridin-3-yl]amino}carbonyl)amino]-3-[3- Found (M − H)⁻= 524.00. (cyclopentyloxy)phenyl]propanoic acid(3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 3 Calculated (M + H)⁺= 545.18; 3-oxo-2,3-dihydropyridazin-4- Found (M + H)⁺ = 544.98.yl]amino}carbonyl)amino]-3-(3,4- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 3 Calculated (M − H)⁻= 507.14; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 506.94.yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5- yl)propanoic acid(3S)-3-[({[2-(2-chlorobenzyl)-5-hydroxy-6-methyl- 10 Calculated (M + H)⁺= 545.18; 3-oxo-2,3-dihydropyridazin-4- Found (M + H)⁺ = 545.01.yl]amino}carbonyl)amino]-3-(3,5- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 70 Calculated (M − H)⁻= 538.10; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 537.95.yl]amino}carbonyl)amino]-3-[4- (trifluoromethoxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 10 Calculated (M − H)⁻= 538.10; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 537.95.yl]amino}carbonyl)amino]-3-[3- (trifluoromethoxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 4 Calculated (M + H)⁺= 486.14; 2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 486.04.yl]amino}carbonyl)amino]-3-(4- methoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 15 Calculated (M −H)⁻ = 520.13; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(6- Found (M −H)⁻ = 520.03. methoxy-2-naphthyl)propanoic acid(3S)-3-{[({1-[2-fluoro-6-(trifluoromethyl)benzyl]-4- 100 Calculated (M −H)⁻ = 520.15; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M −H)⁻ = 519.97. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 10 Calculated (M − H)⁻= 522.10; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 521.96.yl]amino}carbonyl)amino]-3-[3- (trifluoromethyl)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 3 Calculated (M − H)⁻= 484.13; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 484.00.yl]amino}carbonyl)amino]-3-(3- methoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 20 Calculated (M + H)⁺= 510.18; 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M +H)⁺ = 510.05. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy- 4 Calculated (M + H)⁺= 540.19; 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M +H)⁺ = 540.10. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 3 Calculated (M + H)⁺ =540.19; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =540.09. yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 3 Calculated (M − H)⁻= 542.17; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 542.00.yl]amino}carbonyl)amino]-3-(3,5- diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M − H)⁻= 556.19; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 556.01.yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 3 Calculated (M + H)⁺= 530.17; 2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 530.04.yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 15 Calculated (M − H)⁻= 530.17; 2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ = 538.03.yl]amino}carbonyl)amino]-3-[3- (cyclopentyloxy)phenyl]propanoic acid3-(1,1′-biphenyl-4-yl)-3-[({[1-(2-chlorobenzyl)-4- 130 Calculated (M −H)⁻ = 530.15; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M −H)⁻ = 529.96. yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 30 Calculated (M + H)⁺ =580.15; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =580.02. yl]amino}carbonyl)amino]-3-[3-(2,2,2-trifluoroethoxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 15 Calculated (M + H)⁺= 554.13; 2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 554.00.yl]amino}carbonyl)amino]-3-[3-(2,2,2- trifluoroethoxy)phenyl]propanoicacid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl- 3 Calculated (M +H)⁺ = 514.17; 2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 514.05.yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy- 4 Calculated (M + H)⁺= 558.20; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 558.05.yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid

TABLE 7 Mass Spectral Data Compound IC₅₀ (nM) ( m/z)(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 9 Calculated (M +H)⁺ = 500.16; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M + H)⁺ = 500.01. 3-(4-methoxy-3-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 10 Calculated (M +H)⁺ = 554.21; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 554.06. yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M +H)⁺ = 580.19; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =580.07. yl]amino}carbonyl)amino]-3-(6-methoxy-2- naphthyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 12 Calculated (M +H)⁺ = 530.17; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M + H)⁺ = 530.00. 3-(3,5-dimethoxy-4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 12 Calculated (M +H)⁺ = 554.21; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 554.05. yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-propoxybenzyl)-4-hydroxy- 10 Calculated (M +H)⁺ = 528.19; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =528.06. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-isobutoxybenzyl)-4- 22 Calculated (M + H)⁺ =542.21; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =542.06. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 15 Calculated (M + H)⁺ =540.19; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =540.07. yl]amino}carbonyl)amino]-3-(3- propoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 3 Calculated (M +H)⁺ = 540.19; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 540.04. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 4 Calculated(M + H)⁺ = 584.22; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-Found (M + H)⁺ = 584.05. yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 40 Calculated (M +H)⁺ = 592.19; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M + H)⁺ = 592.04. 3-(2′,6′-dimethoxy-1,1′-biphenyl-4-yl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 30 Calculated (M +H)⁺ = 509.16; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M + H)⁺ = 509.03. 3-(1-methyl-1H-indol-7-yl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated (M +H)⁺ = 570.20; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 570.09. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoicacid (3S)-3-[({[1-(2-chloro-6-propoxybenzyl)-4-hydroxy- 5 Calculated(M + H)⁺ = 558.20; 5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =558.03. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-isobutoxybenzyl)-4- 14 Calculated (M + H)⁺ =572.22; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =572.05. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-isopropoxybenzyl)-4- 7 Calculated (M + H)⁺ =558.20; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =558.03. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-{[({1-[2-chloro-6-(2,2,2- 4 Calculated (M + H)⁺ = 598.16;trifluoroethoxy)benzyl]-4-hydroxy-5-methyl-2-oxo- Found (M + H)⁺ =597.99. 1,2-dihydropyridin-3-yl}amino)carbonyl]amino}-3-(3-ethoxyphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 15 Calculated (M +H)⁺ = 502.12; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M + H)⁺ = 501.98. [4-(methylthio)phenyl]propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated (M +H)⁺ = 606.20; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 606.04. yl]amino}carbonyl)amino]-3-(6-methoxy-2-naphthyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 6 Calculated (M +H)⁺ = 498.14; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M + H)⁺ = 498.02. 3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M +H)⁺ = 553.19; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =553.05. yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5- yl)propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 2 Calculated(M + H)⁺ = 542.17; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =542.06. yl]amino}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 3 Calculated (M +H)⁺ = 614.22; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 614.11. yl]amino}carbonyl)amino]-3-(3,5-diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-isopropoxybenzyl)-4- 4 Calculated (M + H)⁺ =558.20; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =558.02. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M +H)⁺ = 558.20; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =558.07. yl]amino}carbonyl)amino]-3-(3- propoxyphenyl)propanoic acid(3S)-3-(3-butoxyphenyl)-3-[({[1-(2-chloro-6- 4 Calculated (M + H)⁺ =572.22; ethoxybenzyl)-4-hydroxy-5-methyl-2-oxo-1,2- Found (M + H)⁺ =572.04. dihydropyridin-3- yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[5-chloro-1-(2-chloro-6-ethoxybenzyl)-4- 3 Calculated (M + H)⁺= 564.13; hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ = 563.99.yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 3 Calculated (M +H)⁺ = 544.19; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M + H)⁺ = 544.06. 3-(3-isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 2 Calculated (M + H)⁺ =524.16; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =524.03. yl]amino}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6- 7 Calculated (M +H)⁺ = 515.19; methyl-3-oxo-2,3-dihydropyridazin-4- Found (M + H)⁺ =515.05. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 3 Calculated (M +H)⁺ = 584.21; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 584.10. yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoic acid(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6- 3 Calculated (M +H)⁺ = 545.18; methyl-3-oxo-2,3-dihydropyridazin-4- Found (M + H)⁺ =545.05. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[2-(2-chloro-6-ethoxybenzyl)-5-hydroxy-6- 2 Calculated (M +H)⁺ = 559.20; methyl-3-oxo-2,3-dihydropyridazin-4- Found (M + H)⁺ =559.04. yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 6 Calculated (M +H)⁺ = 610.23; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 610.14. yl]amino}carbonyl)amino]-3-[3-(cyclopentyloxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 7 Calculated (M + H)⁺ =566.21; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =566.09. yl]amino}carbonyl)amino]-3-[3- (cyclopentyloxy)phenyl]propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated(M + H)⁺ = 526.17; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-Found (M + H)⁺ = 526.07. yl]amino}carbonyl)amino]-3-phenylpropanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 8 Calculated (M + H)⁺ =482.15; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =482.07. yl]amino}carbonyl)amino]-3-phenylpropanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5- 5 Calculated (M +H)⁺ = 512.16; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =512.03. yl]amino}carbonyl)amino]-3-(2,3-dihydro-1-benzofuran-5-yl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo- 4 Calculated (M + H)⁺ =594.21; 2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =594.05. yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M +H)⁺ = 568.15; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =568.00. yl]amino}carbonyl)amino]-3-[3- (trifluoromethyl)phenyl]propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 4 Calculated(M + H)⁺ = 584.14; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =584.01. yl]amino}carbonyl)amino]-3-[3-(trifluoromethoxy)phenyl]propanoic acid(3S)-3-{[({1-[2-chloro-6-(2-methoxyethoxy)benzyl]-4- 6 Calculated (M −H)⁻ = 568.18; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ =568.03. cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid(3S)-3-{[({1-[2-chloro-6-(2-methoxyethoxy)benzyl]-4- 4 Calculated (M −H)⁻ = 598.19; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ =598.01. cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(3-ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 4 Calculated (M +H)⁺ = 538.17; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =538.09. yl]amino}carbonyl)amino]-3-[3- (cyclopropyloxy)phenyl]propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 4 Calculated(M − H)⁻ = 556.19; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =556.02. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 4 Calculated (M −H)⁻ = 526.17; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =526.02. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M − H)⁻= 570.20; hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =570.04. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M − H)⁻= 540.19; hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =540.05. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 25 Calculated (M +H)⁺ = 562.09; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M + H)⁺ = 562.17. (2′-methoxy-1,1′-biphenyl-4-yl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 3 Calculated (M −H)⁻ = 570.20; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =570.00. yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5,6- 4 Calculated (M −H)⁻ = 512.16; dimethyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =512.01. yl]amino}carbonyl)amino]-3-phenylpropanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 5 Calculated (M − H)⁻= 584.22; hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =584.03. yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-ethyl-4- 4 Calculated (M − H)⁻= 526.17; hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =526.00. yl]amino}carbonyl)amino]-3-phenylpropanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 6 Calculated (M −H)⁻ = 592.19; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =592.00. yl]amino}carbonyl)amino]-3-(6-ethoxy-2- naphthyl)propanoic acid(3S)-3-[({[2-(2-chlorobenzyl)-6-ethyl-5-hydroxy-3-oxo- 22 Calculated (M− H)⁻ = 483.14; 2,3-dihydropyridazin-4-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 483.03. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 15 Calculated (M− H)⁻ = 536.20; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =535.99. yl]amino}carbonyl)amino]-3-(3- isobutylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 4 Calculated (M +H)⁺ = 509.16; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M + H)⁺ = 509.05. (1-methyl-1H-indol-6-yl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 4 Calculated (M −H)⁻ = 550.17; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 550.01. yl]amino}carbonyl)amino]-3-[3-(cyclopropyloxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 15 Calculated (M− H)⁻ = 574.17; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =574.02. yl]amino}carbonyl)amino]-3-(6-ethoxy-2- naphthyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 23 Calculated (M −H)⁻ = 526.17; oxo-5-propyl-1,2-dihydropyridin-3- Found (M − H)⁻ =526.04. yl]amino}carbonyl)amino]-3-phenylpropanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 22 Calculated (M −H)⁻ = 584.22; oxo-5-propyl-1,2-dihydropyridin-3- Found (M − H)⁻ =584.09. yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 20 Calculated (M −H)⁻ = 540.19; oxo-5-propyl-1,2-dihydropyridin-3- Found (M − H)⁻ =540.05. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 6 Calculated (M −H)⁻ = 570.20; oxo-5-propyl-1,2-dihydropyridin-3- Found (M − H)⁻ =570.04. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 40 Calculated (M −H)⁻ = 530.15; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(4′- Found (M− H)⁻ = 530.02. methyl-1,1′-biphenyl-4-yl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 4 Calculated (M −H)⁻ = 533.16; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =533.00. yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5- yl)propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl- 3 Calculated(M − H)⁻ = 582.20; 4-hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻= 582.07. yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-5-cyclopropyl- 3 Calculated (M −H)⁻ = 538.17; 4-hydroxy-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =538.06. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-propoxybenzyl)-4-hydroxy-5- 6 Calculated (M −H)⁻ = 526.17; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =526.05. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-methoxybenzyl)-4-hydroxy-5- 3 Calculated (M −H)⁻ = 498.14; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =498.01. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl- 13 Calculated (M −H)⁻ = 548.16; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M − H)⁻ = 548.01. 3-(2-naphthyl)propanoic acid3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5-methyl- 8 Calculated (M −H)⁻ = 576.12; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M − H)⁻ = 576.00. 3-[4-(methylsulfonyl)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 27 Calculated (M −H)⁻ = 560.16; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3′- Found (M− H)⁻ = 560.04. ethoxy-1,1′-biphenyl-4-yl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 20 Calculated (M −H)⁻ = 564.19; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 564.00. yl]amino}carbonyl)amino]-3-[3-(cyclobutyloxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 17 Calculated (M− H)⁻ = 550.17; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =550.02. yl]amino}carbonyl)amino]-3-[3- (cyclobutyloxy)phenyl]propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-6- 3 Calculated (M− H)⁻ = 556.19; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =556.05. yl]amino}carbonyl)amino]-3-(3- isopropoxyphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 10 Calculated (M −H)⁻ = 523.17; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3- Found(M − H)⁻ = 522.99. pyrrolidin-1-ylphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 22 Calculated (M −H)⁻ = 537.19; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3- Found(M − H)⁻ = 537.08. piperidin-1-ylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 22 Calculated (M −H)⁻ = 580.22; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 580.04. yl]amino}carbonyl)amino]-3-[3-(1-ethylpropoxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 20 Calculated (M− H)⁻ = 566.20; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =566.01. yl]amino}carbonyl)amino]-3-[3-(1- ethylpropoxy)phenyl]propanoicacid (3S)-3-(4-chloro-3-isopropoxyphenyl)-3-[({[1-(2- 23 Calculated (M −H)⁻ = 586.15; chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7- Found (M −H)⁻ = 585.92. tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 38 Calculated (M− H)⁻ = 572.14; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =572.00. yl]amino}carbonyl)amino]-3-(4-chloro-3-isopropoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-1,2- 30 Calculated (M −H)⁻ = 530.15; dihydropyridin-3-yl]amino}carbonyl)amino]-3-(3′- Found (M− H)⁻ = 530.02. methyl-1,1′-biphenyl-4-yl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 3 Calculated (M −H)⁻ = 533.16; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =532.97. yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-6- yl)propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-5- 3 Calculated (M− H)⁻ = 551.17; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =551.02. yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-6- yl)propanoicacid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 23 Calculated(M − H)⁻ = 560.16; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-Found (M − H)⁻ = 560.01. (4′-methoxy-1,1′-biphenyl-4-yl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 55 Calculated (M +H)⁺ = 546.18; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M + H)⁺ = 546.11. (2′-methyl-1,1′-biphenyl-4-yl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 3 Calculated (M −H)⁻ = 560.16; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =560.00. yl]amino}carbonyl)amino]-3-(6-methoxy-2- naphthyl)propanoic acid(3S)-3-(4-chloro-3-ethoxyphenyl)-3-[({[1-(2-chloro-6- 25 Calculated (M −H)⁻ = 572.14; methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found(M − H)⁻ = 571.94. cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 30 Calculated (M− H)⁻ = 558.12; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =557.77. yl]amino}carbonyl)amino]-3-(4-chloro-3- ethoxyphenyl)propanoicacid (3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 4 Calculated(M + H)⁺ = 582.24; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-Found (M + H)⁺ = 582.10. yl]amino}carbonyl)amino]-3-(3-isobutylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-ethoxybenzyl)-4-hydroxy-5- 4 Calculated (M +H)⁺ = 514.17; methyl-2-oxo-1,2-dihydropyridin-3- Found (M + H)⁺ =514.08. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 134 Calculated (M +H)⁺ = 534.11; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-[4- Found(M + H)⁺ = 534.07. (methylsulfonyl)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 225 Calculated(M + H)⁺ = 594.09; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺= 593.98. yl]amino}carbonyl)amino]-3-(2,4-dichloro-3-ethoxyphenyl)propanoic acid (3S)-3-{[({1-[2-chloro-5-(piperidin-1- 27Calculated (M − H)⁻ = 615.17;ylsulfonyl)benzyl]-4-hydroxy-5-methyl-2-oxo-1,2- Found (M − H)⁻ =615.04. dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid (3S)-3-{[({1-[2-chloro-5-(pyrrolidin-1- 15Calculated (M − H)⁻ = 601.15;ylsulfonyl)benzyl]-4-hydroxy-5-methyl-2-oxo-1,2- Found (M − H)⁻ =601.03. dihydropyridin-3-yl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 2 Calculated (M +H)⁺ = 582.20; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 582.10. yl]amino}carbonyl)amino]-3-[3-(cyclopropyloxy)phenyl]propanoic acid(3S)-3-{[({1-[2-chloro-6-(cyclopentylmethoxy)benzyl]- 20 Calculated (M −H)⁻ = 566.20; 4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M −H)⁻ = 566.09. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-{[({1-[2-(benzyloxy)-6-chlorobenzyl]-4- 10 Calculated (M − H)⁻ =574.17; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =574.01. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 3 Calculated (M +H)⁺ = 604.16; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =604.02. yl]amino}carbonyl)amino]-3-(3-chloro-4,5-diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 500 Calculated (M +H)⁺ = 652.14; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 651.98. yl]amino}carbonyl)amino]-3-(2,4-dichloro-3,5-diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 450 Calculated(M + H)⁺ = 638.12; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺= 637.97. yl]amino}carbonyl)amino]-3-(2,4-dichloro-3,5-diethoxyphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 9 Calculated (M +H)⁺ = 552.19; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =552.10. yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2- 4 Calculated (M +H)⁺ = 596.21; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 596.11. yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 10 Calculated (M +H)⁺ = 566.20; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 566.12. yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 13 Calculated (M −H)⁻ = 544.16; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 544.00. (2,4-diethoxypyrimidin-5-yl)propanoic acid(3S)-3-[({[1-(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 5 Calculated (M −H)⁻ = 572.13; 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M − H)⁻ = 571.97. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoicacid (3S)-3-[3-(cyclopropylmethoxy)phenyl]-3-[({[1-(2,3- 7 Calculated (M− H)⁻ = 628.16; dichloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7- Found(M − H)⁻ = 627.98. tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 3 Calculated (M −H)⁻ = 602.15; 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M − H)⁻ = 601.99. yl]amino}carbonyl)amino]-3-(3- ethoxyphenyl)propanoicacid (3S)-3-[({[1-(2,3-dichloro-6-ethoxybenzyl)-4-hydroxy- 5 Calculated(M − H)⁻ = 616.16; 2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-Found (M − H)⁻ = 616.01. yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoic acid(3S)-3-({[[1-(2-chlorobenzyl)-4-methoxy-2-oxo-1,2- 2000 Calculated (M −H)⁻ = 482.14; dihydropyridin-3-yl](methyl)amino]carbonyl}amino)-3- Found(M − H)⁻ = 482.07. (4-methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 15 Calculated (M −H)⁻ = 560.16; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 559.98. (2′-methoxy-1,1′-biphenyl-3-yl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 20 Calculated (M −H)⁻ = 458.11; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(5- Found(M − H)⁻ = 457.99. methyl-2-furyl)propanoic acid3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-5-methyl- 43 Calculated (M +H)⁺ = 548.13; 2-oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]- Found(M + H)⁺ = 548.07. 3-[4-(methylsulfonyl)phenyl]propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 5 Calculated (M − H)⁻= 470.11; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ = 469.96.yl]amino}carbonyl)amino]-3-(2-furyl)propanoic acid3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2-oxo- 4 Calculated (M − H)⁻= 444.10; 1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3-(2- Found (M −H)⁻ = 443.91. furyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 18 Calculated (M− H)⁻ = 548.12; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =548.00. yl]amino}carbonyl)amino]-3-[4- (trifluoromethyl)phenyl]propanoicacid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 5 Calculated(M − H)⁻ = 494.15; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻= 494.02. yl]amino}carbonyl)amino]-3-(3- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 10 Calculated (M− H)⁻ = 548.12; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =547.99. yl]amino}carbonyl)amino]-3-[3- (trifluoromethyl)phenyl]propanoicacid (3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 9 Calculated(M − H)⁻ = 508.16; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻= 508.02. yl]amino}carbonyl)amino]-3-(3,5- dimethylphenyl)propanoic acid(3S)-3-[3,5-bis(trifluoromethyl)phenyl]-3-[({[1-(2- 130 Calculated (M −H)⁻ = 615.11; chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found(M − H)⁻ = 615.99. cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]propanoic acid(3S)-3-{[({1-[2-chloro-5-(trifluoromethyl)benzyl]-4- 6 Calculated (M −H)⁻ = 536.12; hydroxy-5-methyl-2-oxo-1,2-dihydropyridin-3- Found (M −H)⁻ = 535.99. yl}amino)carbonyl]amino}-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chloro-5-fluorobenzyl)-4-hydroxy-5- 5 Calculated (M −H)⁻ = 486.12; methyl-2-oxo-1,2-dihydropyridin-3- Found (M − H)⁻ =485.97. yl]amino}carbonyl)amino]-3-(4- methylphenyl)propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-5-methyl-2- 2 Calculated (M −H)⁻ = 525.19; oxo-1,2-dihydropyridin-3-yl]amino}carbonyl)amino]-3- Found(M − H)⁻ = 525.00. [3-(diethylamino)phenyl]propanoic acid3-(1,1′-biphenyl-4-yl)-3-[({[1-(2-chlorobenzyl)-4- 30 Calculated (M −H)⁻ = 556.16; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ =555.99. cyclopenta[b]pyridin-3- yl]amino}carbonyl)amino]propanoic acid(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7- 8 Calculated (M +H)⁺ = 522.17; tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M + H)⁺ =522.03. yl]amino}carbonyl)amino]-3-(2,3-dihydro-1H-inden-5- yl)propanoicacid (3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2- 10 Calculated(M + H)⁺ = 536.19; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-Found (M + H)⁺ = 536.08.yl]amino}carbonyl)amino]-3-(2,3-dihydro-1H-inden-5- yl)propanoic acidN-{1-[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl- 6000 Calculated (M +H)⁺ = 494.17; 2-oxo-1,2-dihydro-3-pyridinyl}-N′-[(1S)-1-(4- Found (M +H)⁺ = 494.01. methylphenyl)-2-(1H-1,2,3,4-tetraazol-5-yl)ethyl]urea(3S)-3-[1,1′-biphenyl]-3-yl-3-{[({1-[(2- 17 Calculated (M − H)⁻ =556.16; chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7- Found (M − H)⁻ =556.01. tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 13 Calculated (M −H)⁻ = 564.11; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 564.01. yl}amino)carbonyl]amino}-3-{4-[(trifluoromethyl)oxy]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 13 Calculated (M −H)⁻ = 546.12; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 545.97. yl}amino)carbonyl]amino}-3-{4-[(difluoromethyl)oxy]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 10 Calculated (M −H)⁻ = 564.11; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 563.98. yl}amino)carbonyl]amino}-3-{3-[(trifluoromethyl)oxy]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 5 Calculated (M − H)⁻= 546.12; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 546.01. yl}amino)carbonyl]amino}-3-{3-[(difluoromethyl)oxy]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 4 Calculated (M − H)⁻= 596.12; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 596.02. yl}amino)carbonyl]amino}-3-{3-[(1,1,2,2-tetrafluoroethyl)oxy]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 11 Calculated (M −H)⁻ = 538.17; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 538.04. yl}amino)carbonyl]amino}-3-[3,5-dimethyl-4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 5 Calculated (M + H)⁺= 549.19; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M +H)⁺ = 549.02. yl}amino)carbonyl]amino}-3-(1-ethyl-1H-indol-5-yl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 7Calculated (M − H)⁻ = 516.11;oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M − H)⁻ =516.01. yl}amino)carbonyl]amino}-3-(3,5- difluorophenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 3 Calculated (M − H)⁻= 528.13; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 528.00. yl}amino)carbonyl]amino}-3-[3-fluoro-4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 17 Calculated (M −H)⁻ = 522.18; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]Pyridin-3- Found (M− H)⁻ = 522.04. yl}amino)carbonyl]amino}-3-(4- propylphenyl)propanoicacid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 20 Calculated (M− H)⁻ = 536.20; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ =536.06. cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-propylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 267 Calculated (M −H)⁻ = 468.13; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 468.00.pyridinyl}amino)carbonyl]amino}-3-(2- methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 25 Calculated (M +H)⁺ = 522.18; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M + H)⁺ = 522.04. yl}amino)carbonyl]amino}-3-(4-cyclopropylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 22 Calculated (M −H)⁻ = 505.13; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 504.98.pyridinyl}amino)carbonyl]amino}-3-(3- quinolinyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 22 Calculated (M −H)⁻ = 531.14; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 530.99. yl}amino)carbonyl]amino}-3-(3-quinolinyl)propanoic acid3-({[(1-{[2-chloro-6-(ethyloxy)phenyl]methyl}-4- 8 Calculated (M − H)⁻ =488.12; hydroxy-5-methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 487.98.pyridinyl)amino]carbonyl}amino)-3-(2- furanyl)propanoic acid(3S)-3-[2,4-bis(ethyloxy)-5-pyrimidinyl]-3-{[({1-[(2- 15 Calculated (M −H)⁻ = 570.18; chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7 Found (M −H)⁻ = 570.14. tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 19 Calculated (M + H)⁺= 536.20; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M + H)⁺ = 536.07.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-cyclopropylphenyl)propanoic acid(3R)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 15 Calculated (M −H)⁻ = 418.12; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 418.00. yl}amino)carbonyl]amino}butanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 8 Calculated (M − H)⁻= 508.16; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 508.06. yl}amino)carbonyl]amino}-3-(4- ethylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 17 Calculated (M −H)⁻ = 522.17; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 522.06. yl}amino)carbonyl]amino}-3-[4-(1-methylethyl)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 30 Calculated (M −H)⁻ = 482.14; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 482.00.pyridinyl}amino)carbonyl]amino}-3-(4- ethylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 175 Calculated (M −H)⁻ = 496.16; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 496.01.pyridinyl}amino)carbonyl]amino}-3-[4-(1- methylethyl)phenyl]propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 6 Calculated (M− H)⁻ = 510.14; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 510.00.pyridinyl}amino)carbonyl]amino}-3-[4- (cyclopropyloxy)phenyl]propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 12 Calculated (M− H)⁻ = 496.16; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 495.99.pyridinyl}amino)carbonyl]amino}-3-(4- propylphenyl)propanoic acid3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 35 Calculated (M − H)⁻ =494.15; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 494.01.pyridinyl}amino)carbonyl]amino}-3-(4- cyclopropylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 18 Calculated (M −H)⁻ = 494.15; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 494.02.pyridinyl}amino)carbonyl]amino}-3-(2,3-dihydro- 1H-inden-5-yl)propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 13 Calculated (M− H)⁻ = 597.19; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M − H)⁻ = 597.01. yl}amino)carbonyl]amino}-3-(9-ethyl-9H-carbazol-3-yl)propanoic acid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 23Calculated (M − H)⁻ = 571.17; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻= 570.99. pyridinyl}amino)carbonyl]amino}-3-(9-ethyl-9H-carbazol-3-yl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M − H)⁻= 547.17; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ = 547.04.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1-methyl-1H-indol-5-yl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M − H)⁻= 560.14; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ = 560.03.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(difluoromethyl)oxy]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 25 Calculated (M −H)⁻ = 574.17; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 574.00.pyridinyl}amino)carbonyl]amino}-3-[2-(ethyloxy)[1,1′-biphenyl]-4-yl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 20 Calculated (M −H)⁻ = 600.19; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 600.01. yl}amino)carbonyl]amino}-3-[2-(ethyloxy)[1,1′-biphenyl]-4-yl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 20 Calculated (M −H)⁻ = 544.16; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 544.04.pyridinyl}amino)carbonyl]amino}-3-(2′-methyl[1,1′-biphenyl]-3-yl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 18 Calculated (M −H)⁻ = 544.16; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 544.00.pyridinyl}amino)carbonyl]amino}-3-(3′-methyl[1,1′-biphenyl]-3-yl)propanoic acid(3S)-3-({[(1-{[2-chloro-6-tetrahydro-1(2H)- 90 Calculated (M − H)⁻ =551.21; pyridinylphenyl]methyl}-4-hydroxy-5-methyl-2-oxo- Found (M − H)⁻= 551.06. 1,2-dihydro-3-pyridinyl)amino]carbonyl}amino)-3-(4-methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 23 Calculated (M −H)⁻ = 544.16; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 543.99.pyridinyl}amino)carbonyl]amino}-3-(4′-methyl[1,1′-biphenyl]-3-yl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 3 Calculated (M − H)⁻= 551.21; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 551.05. yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 20 Calculated (M −H)⁻ = 504.11; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 503.96.pyridinyl}amino)carbonyl]amino}-3-[3- (difluoromethyl)phenyl]propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 16 Calculated (M− H)⁻ = 498.12; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found(M − H)⁻ = 498.02. yl}amino)carbonyl]amino}-3-(3- fluorophenyl)propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2 9 Calculated (M −H)⁻ = 498.12; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)⁻ = 498.01. yl}amino)carbonyl]amino}-3-(4- fluorophenyl)propanoicacid N-{1-[(2-chlorophenyl)methyl]-4-hydroxy-5-methyl- >10000 Calculated(M − H)⁻ = 464.12; 2-oxo-1,2-dihydro-3-pyridinyl}-N′-[(R)-phenyl(1H-Found (M − H)⁻ = 464.01. 1,2,3,4-tetraazol-5-yl)methyl]urea(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 4 Calculated (M − H)⁻= 521.16; hydroxy-5-methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 521.00.pyridinyl}amino)carbonyl]amino}-3-(1-methyl-1H- indol-5-yl)propanoicacid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 10 Calculated (M− H)⁻ = 565.14; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ =565.04. cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 4 Calculated (M − H)⁻= 508.16; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ = 508.03.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(3-methylphenyl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 17 Calculated (M − H)⁻= 494.15; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ = 494.09.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3- phenylpropanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 8 Calculated (M − H)⁻= 496.13; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 495.99. yl}amino)carbonyl]amino}-3-(3- hydroxyphenyl)propanoicacid (3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 9 Calculated (M− H)⁻ = 470.11; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 469.98.pyridinyl}amino)carbonyl]amino}-3-(3- hydroxyphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 50 Calculated (M −H)⁻ = 558.18; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 558.00.pyridinyl}amino)carbonyl]amino}-3-(3′,5′-dimethyl[1,1′-biphenyl]-3-yl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 15 Calculated (M −H)⁻ = 455.12; methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 454.00.pyridinyl}amino)carbonyl]amino}-3-phenylpropanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 3 Calculated (M − H)⁻= 573.12; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 572.98. yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl}propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M − H)⁻= 587.14; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ = 586.98.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 4 Calculated (M − H)⁻= 530.13; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)⁻ = 530.03. yl}amino)carbonyl]amino}-3-[3-(difluoromethyl)phenyl]propanoic acid(2S,3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy- 1500 Calculated (M −H)⁻ = 482.15; 5-methyl-2-oxo-1,2-dihydro-3- Found (M − H)⁻ = 481.99.pyridinyl}amino)carbonyl]amino}-2-methyl-3-(4- methylphenyl)propanoicacid (3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 15 Calculated (M− H)⁻ = 522.18; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)⁻ =522.04. cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(4-ethylphenyl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 3 Calculated (M − H)⁻= 550.17; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)− = 550.05. yl}amino)carbonyl]amino}-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 3 Calculated (M − H)⁻= 542.15; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)− = 542.00.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-fluoro-4-(methyloxy)phenyl]propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 11 Calculated (M − H)⁻= 578.13; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)− = 578.02.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(trifluoromethyl)oxy]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 1.6 Calculated (M −H)⁻ = 587.14; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M− H)− = 586.99. yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 1.3 Calculated (M −H)⁻ = 601.15; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)− =601.00. cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2- 1 Calculated (M − H)⁻= 601.15; oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3- Found (M −H)− = 601.00. yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 1 Calculated (M − H)⁻= 615.17; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)− = 615.04.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 25 Calculated (M −H)⁻ = 548.14; methyl-2-oxo-1,2-dihydro-3- Found (M − H)− = 547.96.pyridinyl}amino)carbonyl]amino}-3-(2′-fluoro[1,1′-biphenyl]-3-yl)propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 157 Calculated (M −H)⁻ = 598.14; methyl-2-oxo-1,2-dihydro-3- Found (M − H)− = 597.97.pyridinyl}amino)carbonyl]amino}-3-[2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]propanoic acid(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-5- 10 Calculated (M −H)⁻ = 472.11; methyl-2-oxo-1,2-dihydro-3- Found (M − H)− = 471.98.pyridinyl}amino)carbonyl]amino}-3-(2- fluorophenyl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 2 Calculated (M − H)⁻= 533.16; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)− = 533.01.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1H-indol-5-yl)propanoic acid(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4- 11 Calculated (M − H)⁻= 530.13; hydroxy-2-oxo-2,5,6,7-tetrahydro-1H- Found (M − H)− = 530.00.cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(3,5-difluorophenyl)propanoic acid

All references cited are hereby incorporated by reference.

The present invention is illustrated by way of the foregoing descriptionand examples. The foregoing description is intended as a non-limitingillustration, since many variations will become apparent to thoseskilled in the art in view thereof. It is intended that all suchvariations within the scope and spirit of the appended claims beembraced thereby.

Changes can be made in the composition, operation and arrangement of themethod of the present invention described herein without departing fromthe concept and scope of the invention as defined in the followingclaims:

1. A compound of the structure:

wherein

is

wherein each Z is independently selected from the group consisting ofCR³⁰ and C(R³¹)(R³²); z is an integer of from 3 to 5: T is (CH₂)_(b)wherein b is 0; L is (CH₂)_(n) wherein n is 0; B and R⁶ areindependently selected from the group consisting of hydrogen and alkyl;R⁴ is selected from the group consisting of aryl, biaryl and alkylwherein R⁴ can be unsubstituted or substituted with one or more electrondonating or electron withdrawing groups selected from the groupconsisting of alkyl, alkoxy, halogen, —O(haloalkyl), haloalkyl,—O(cycloalkylalkyl), cycloalkyl, dialkylamino, —O(cycloalkyl,—NHSO₂(alkyl), —N(alkyl)SO₂(alkyl); R⁵ is selected from the groupconsisting of aralkyl, —O(aryl), —NH(aralkyl), wherein R⁵ can beunsubstituted or substituted with one or more electron donating orelectron withdrawing groups selected from the group consisting ofhalogen, —CN, alkyl, alkoxy or alkoxyalkoxy; and R⁷, R³⁰, R³¹ and R³²when present are each hydrogen; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 having the structure:

wherein Z is selected from the group consisting of CH₂ and CH; z is aninteger of from 3 to 5; R¹⁸ is aralkyl, wherein R¹⁸ can be unsubstitutedor substituted with one or more electron donating or electronwithdrawing groups selected from the group consisting of halogen, alkyl,alkoxy or alkoxyalkoxy; or a pharmaceutically acceptable salt thereof.3. The compound of claim 1 having the structure:

wherein R¹⁸ is aralkyl wherein R¹⁸ can be unsubstituted or substitutedwith one or more electron donating or electron withdrawing groupsselected from the group consisting of halogen, alkyl, alkoxy oralkoxyalkoxy; R²⁷ is selected from the group consisting of alkyl,alkoxy, halogen, —O(haloalkyl), haloalkyl, —O(cycloalkylalkyl),cycloalkyl, dialkylamino, —O(cycloalkyl), —NHSO₂(alkyl),—N(alkyl)SO₂(alkyl); and h is an integer of from 0 to 5; or apharmaceutically acceptable salt thereof.
 4. A compound selected fromthe group consisting of:(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-3quinolinyl}amino)carbonyl]amino}-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-methylbenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-isopropoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-ethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-diethoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-propoxyphenyl)propanoicacid,(3S)-3-[({[1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-phenylpropanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-yl)propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(1-methyl-1H-indol-5-yl)propanoicacid,(3S)-3-[({[1-(6-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropyloxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoicacid,(3S)-3-{[([1-(2-chloro-6-ethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-[3-(cyclopropylmethoxy)phenyl]propanoicacid,(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3-methylphenyl)propanoicacid,(3S)-3-{[([1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(3,5-dimethylphenyl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(difluoromethyl)oxy]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(1,1,2,2-tetrafluoroethyl)oxy]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{1-ethyl-1H-indol-5-yl)propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-[1-methyl-1H-indol-5-yl)propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-[3-(diethylamino)phenyl]propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[(methylsulfonyl)amino]phenyl1 propanoic acid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[methyl(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoicacid,(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-{3-[ethyl(methylsulfonyl)amino]phenyl}propanoicacid, and(3S)-3-{[({1-[(2-chloro-6-methylphenyl)methyl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl}amino)carbonyl]amino}-3-(1H-indol-5-yl)propanoicacid. 5.(3S)-3-[({[1-(2-chlorobenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-3-yl]amino}carbonyl)amino]-3-(4-methylphenyl)propanoic acid and pharmaceutically acceptable salts thereof.
 6. Apharmaceutical composition comprising a therapeutically effective amountof the compound of claim 1 and a pharmaceutically acceptable carrier. 7.A method for treating asthma, multiple sclerosis or inflammatory boweldiseases in a mammal comprising administering to said mammal atherapeutically effective amount of a compound of claim 1.